Kappa agonist compounds, pharmaceutical formulations and method of prevention and treatment of pruritus therewith

ABSTRACT

The compounds of formulae IIA, the structure:whereinR1, R2, and X4, X5, n are as described in the specification.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No.09/372,191, filed Aug. 11, 1999, now U.S. Pat. No. 6,239,154, issued onMay 29, 2001, which is a continuation-in-part of U.S. application Ser.No. 09/150,369, filed Sep. 9, 1998, now U.S. Pat. No. 6,303,611, issuedon Oct. 16, 2001, which is a continuation-in-part of U.S. applicationSer. No. 09/034,661, filed Mar. 3, 1998, now U.S. Pat. No. 5,945,443,issued on Aug. 31, 1999, which is a divisional of U.S. application Ser.No. 08/899,086, filed Jul. 23, 1997, now U.S. Pat. No. 5,744,458, issuedon Apr. 28, 1998, which is a divisional of U.S. application Ser. No.09/796,078, filed Feb. 5, 1997, now U.S. Pat. No. 5,688,955, issued onNov. 18, 1997, which is a continuation-in-part of U.S. application Ser.No. 08/612,680, filed Mar. 8, 1996, now U.S. Pat. No. 5,646,151, issuedon Jul. 8, 1997.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to compounds, to processes of their preparation,to pharmaceutical compositions containing them and to their medical useas agonists at kappa opioid receptors.

The present invention also relates to compositions and method for thetreatment and/or prevention of itch, also known as pruritus, which hasmany causes. The compositions, which are formulated for topical andsystemic administration, contain kappa opiate receptor agonists that aresubstantially devoid of central nervous system effects, and, thus, havevery little, if any potential for producing side effects associated withcentrally acting kappa opiate receptor agonists.

2. Reported Developments

A) Kappa (κ)-receptor Agonists as Analgesics

Opium and its derivatives are potent analgesics that also have otherpharmacological effects, and exert their effects by interacting withhigh-affinity receptors.

It has been shown by investigators that there are at least three majoropioid receptor types in the central nervous system (hereinafter CNS)and in the periphery. These receptors, known as mu (μ), delta (δ) andkappa (κ), have distinct pharmacological profiles, anatomicaldistributions and functions. [See, for example: Wood, P. L.,Neuropharmacology, 21, 487-497, 1982; Simon, E., J. Med. Res. Rev., 11,357-374, 1991; Lutz et al., J. Recept. Res. 12, 267-286; and Mansour etal., Opioid I, ed. Herz,. A. (Springer, Berlin) pp. 79-106, 1993.] The δreceptors are abundant in CNS and mediate analgesia, gastrointestinalmotility and various hormonal functions. The μ receptors bindmorphine-like drugs and mediate the opiate phenomena associated withmorphine, including analgesia, opiate dependence, cardiovascular andrespiratory functions, and several neuroendocrine effects.

The κ receptors have a wide distribution in CNS and mediate a spectrumof functions including the modulation of drinking, water balance, foodintake, gut motility, temperature control and various endocrinefunctions. They also produce analgesia. [See, for example: Leander etal., J. Pharmacol Exp. Ther. 234, 463-469, 1985; Morley et al., Peptides4, 797-800, 1983; Manzanares et al., Neuroendocrinology 52, 200-205,1990; and Iyengar et al., J. Pharmacol. Exp. Ther., 238, 429-436, 1986.]

Most clinically used opioid analgesics such as morphine and codeine actas μ receptor agonists. These opioids have well-known, undesirable andpotentially dangerous dependence forming side effects. Compounds whichare κ-receptor agonists act as analgesics through interaction with κopioid receptors. The advantage of these agonists over the classical μreceptor agonists, such as morphine, lies in their ability to causeanalgesia while being devoid of morphine-like behavioral effects andaddiction liability.

A large number of classes of compounds which act as agonists at κ opioidreceptors have been described in the art including the followingillustrative classes of compounds.

U.S. Pat. No. 4,065,573 discloses 4-amino-4-phenylcyclohexane ketalcompounds having analgesic activity.

U.S. Pat. No. 4,212,878 discloses phenylacetamide derivatives havinganalgesic properties and reduced physical dependence liabilityproperties, relative to morphine and methadone.

U.S. Pat. No. 4,145,435 disclosesN-(2-amino-cycloaliphatic)-phenylacetamide compounds having analgesicactivity and narcotic antagonist activity.

U.S. Pat. No. 4,098,904 discloses N-(2-amino-cycloaliphatic)-benzoamidesand naphthamides useful for relieving pain.

U.S. Pat. No. 4,359,476 discloses substituted cycloalkane-amides usefulas analgesics and having low abuse liability.

U.S. Pat. No. 4,438,130 discloses 1-oxa-, aza- and thia-spirocycliccompounds having analgesic activity, low physical dependence and abuseliability properties and little dysphoric inducing properties.

U.S. Pat. No. 4,663,343 discloses substitutednaphthalenyloxy-1,2-diaminocyclohexyl amides as analgesics.

U.S. Pat. No. 4,906,655 discloses 1,2-cyclohexylaminoaryl amides havinghigh kappa-opioid affinity, selectivity and potency and useful asanalgesics, diuretics, anti-inflammatory and psychotherapeutic agents.

B) Kappa (κ)-receptor Agonists as Anti-Pruritic Agents

The prior art has investigated the physiology and treatment of pruritusas illustrated hereunder.

Itch is a well known sensory state associated with the desire toscratch. As with pain, itch can be produced by a variety of chemical,mechanical, thermal or electrical stimuli. In addition to the differencein the sensory quality of itch and pain, they also differ in that (1)itch, unlike pain, can only be evoked from the superficial layers ofskin, mucosa, and conjunctiva, and (2) itch and pain usually do notoccur simultaneously from the same skin region; in fact, mildly painfulstimuli, such as scratching, are effective in eliminating itch. Inaddition, the application of histamine to skin produces itch but notpain. Itch and pain are further dissociated pharmacologically: itchappears to be insensitive to opiate and non-steroidal anti-inflammatorydrug (NSAID) treatment, both of which are effective in treating pain.

Although itch and pain are of a class in that both are modalities ofnociception transmitted by small unmyelinated C fibers, evidence thatitch is not just a variety of low-threshold pain is overwhelming. Itchleads to the reflex or urge to scratch; pain leads to withdrawal. Itchoccurs only in the skin; pain arises from deeper structures as well.Heat may stop pain but usually increases pain. Removal of the epidermiseliminates itch but causes pain. Analgesics, particularly opioids,relieve pain but often cause itch (see, for example J. Am. Acad. Derm.24: 309-310, 1991). There can be no doubt that itching is of eminentclinical importance; many systemic and skin diseases are accompanied bypersistent or recurrent itch attacks. Current knowledge suggests thatitch has several features in common with pain but exhibits intriguingdifferences as well (see, for example, W. Magerl, IASP Newsletter, pp.4-7, September/October 1996).

McMahon et al. (TINS, Vol. 15, No. 12, pp. 497-501, 1992) provides adescription of stimuli (Table a) and a comparison of the establishedfeatures of itch and pain (Table b):

TABLE a Stimuli that can elicit or augment itch Physical Mechanical.Lighttouch, pressure, suction. Thermal. Warming. Electrical. Focaltranscutaneous repetitive stimulation, transcutaneous con- stant currentstimulation, intraneural microstimulation. Chemical Non-specificirritants. Acids, alkalis. Inflammatory mediators. Histamine,kallikrein, bradykinin, prostaglandins. Histamine-releasing substances.Compound 48/80, protamine, C3a. Peptidases. Mucunain, papain, trypsin,mast cell chymase. Neuropeptides. Substance P, vasoactive intestinalpolypeptide, neurotensin, secretin. Opioids. Morphine, β-endorphin,enkephalin analogues.

TABLE b Comparison of the establisbed features of itch and pain ITCHPAIN Psychophysiology Tissue Skin. Mucous membranes Most tissuesStimulus See Table a Many stimuli Intraneural Occasionally Yesmicrostimulation Secondary sensations Alloknesis (itchy skin)Hyperalgesia Psychogenic Pronounced Present modification CounterstimuliScratching, pain, cooling Tactile stimuli, cooling NeurophysiologyPrimary afferent C- and Aδ-fibres C- and Aδ-fibres neurones Flare sizeLarge Small Spinal pathway Anterolateral funiculus Anterolateralfuniculus Protective reflexes Scratching, sneezing Flexion, guardingAutonomic reflexes Yes Yes Pharmacology Capsaicin sensitivity YesChemogenic pain; yes NSAID sensitivity Probably not Yes Morphinesensitivity No Yes Abbreviation: NSAID, non-steroidal anti-inflammatorydrugs.

Experimental focal itch stimuli are surrounded by a halo of seeminglyunaffected tissue where light tactile stimuli are capable of elicitingitch-like sensations. The term itchy skin or alloknesis has been coinedfor these secondary sensations that are reminiscent of the features ofsecondary hyperalgesia evolving around a painful focus. A crucialobservation is that itch and pain usually do not coexist in the sameskin region and a mild noxious stimulus such as scratching is in factthe singly most effective way to abolish itch. This abolition of itchcan be prolonged producing an ‘antipruritic state’. Although mildscratch is often not painful, microneurograpic recordings from humanshave directly determined that such stimuli are among the most effectiveways to excite cutaneous unmyelinated nociceptive afferents. (See, forexample:

Shelly, W. B. and Arthur, R. P. (1957) Arch. Dermatol. 76, 296-323;

Simone, D. A. et al. (1987) Somatosens. Res. 5, 81-92;

Graham, D. T. , Goodell, H. and Wolff, H. G. (1951) J. Clin. Invest. 30,37-49;

Simone, D. A., Alreja, M. and LaMotte, R. H. (1991) Somatosens Mot. Res.8, 271-279;

Torebjörk, E (1985) Philos. Trans. R. Soc. London Ser. B 308, 227-234;and

Vallbo, A. B., Hagbarth, K. E., Torebjörk, H. E. and Wallin, B. G.(1979) Physiol. Rev. 59, 919-957).

Physiologically, there is evidence that substance P released fromnociceptor terminals can cause the release of histamine from mast cells.Activation of mast cells, with release of the pruritogen histamine,occurs in immediate type hypersensitivity diseases, such as anaphylacticreactions and urticaria. Urticarial eruptions are distinctly pruriticand can involve any portion of the body, and have a variety of causesbeyond hypersensitivity, including physical stimuli such as cold, solarradiation, exercise and mechanical irritation. Other causes of pruritusinclude: chiggers, the larval form of which secretes substance thatcreates a red papule that itches intensely; secondaryhyperparathyroidism associated with chronic renal failure; cutaneouslarva migrans, caused by burrowing larvae of animal hookworms; dermalmyiasis, caused by maggots of the horse botfly, which can afflicthorseback riders; onchocerciasis (“river blindness”) caused by filarialnematodes; pediculosis, caused by lice infestations; enterobiasis(pinworm) infestations, which afflict about 40 million Americans,particularly school children; schistosome dermatitis (swimmer's itch);and asteatotic eczema (“winter itch”). The role of histamine or otherendogenous pruritogens in mediating itch associated with these and otherpruritic conditions, such as atopic dermatitis, it is not yet wellestablished. For atopic dermatitis, in particular, it appears that itchis not inhibited by antihistamines, but by cyclosporin A, a drug whichinhibits the production of cytokines which have been proposed aspotential pruritogens.

Current therapies for the treatment of itch include a variety of topicaland systemic agents, such as steroids, antihistamines, and somepsychotherapeutic tricyclic compounds, such as doxepin hydrochloride.Many such agents are listed in PDR Generics (see Second Edition, 1996,p. cv for a listing of said agents). The limitations of these agents arewell known to medical practitioners, and are summarized in the“Warnings” and “Precautions” sections for the individual agents listedin PDR Generics. In particular, the lack of complete efficacy ofantihistamines is well known, but antihistamines are frequently used indermatology to treat pruritus due to urticaria, atopic dermatitis,contact dermatitis, psoriasis, and a variety of other conditions.Although sedation has been a frequent side effect of conventionalsystemically administered antihistamines, a new generation ofantihistamines have been developed that are nonsedating, apparently dueto their inability to cross the blood-brain barrier.

Intravenous administration of opiate analgesics, such as morphine andhydromorphone has been associated with pruritus, urticaria, other skinrashes, wheal and flare over the vein being injected. These itch anditch-related reactions are believed to be due to a histamine-releasingproperty of these opiates, via mast cell degranulation. These opiatesare thought to act upon the mu subtype of opiate receptor, but thepossibility of interactions at the other principal opiate receptorsubtypes (delta and kappa) cannot be excluded since these and otherpruritogenic analgesics are not pure mu agonists. The cellular loci ofthe receptor type(s) mediating the itching effect is not known, althoughthe mast cell is a possible candidate since opiates cause histaminerelease from these cells. However, some investigators have suggestedthat the frequent inability of antihistamines to block morphine-induceditching suggests a non-histaminergic mediation of opiate-induceditching—a mechanism which could involve central opiate receptors.Although i.v. morphine only occasionally results in generalized itching(in about 1% of patients), pruritus is more prevalent in opiateanalgesia with epidural (8.5%) or intraspinal (45.8%) administration.(See, for example: Bernstein et al., “Antipruritic Effect of an OpiateAntagonist, Naloxone Hydrochloride”, The Journal of InvestigativeDermatology, 78:82-83, 1982; and Ballantyne et al., “Itching afterepidural and spinal opiates”, Pain, 33: 149-160, 1988.)

To date, treatment with opiates has not only proven useless in thetreatment of itch, but appears to exacerbate itch in man. The consistentfindings form human studies indicate that whether by central orperipheral mechanisms, opiates appear to promote rather than preventitching, and that opiate antagonists have anti-pruritic activity.

Human clinical studies have generally shown that opiates cause itchingand there is evidence that these effects can be reproduced in animalmodels, where itching sensations per se cannot be reported, butscratching behavior can be observed. (See, for example: Thomas et al.,“Microinjection of morphine into the rat medullary dorsal horn producesa dose-dependent increase in facial-scratching”, Brain Research, 195:267-270, 1996; Thomas et al., “Effects of central administration ofopioids on facial scratching in monkeys”, Brain Res., 585: 315-317,1992; and Thomas et al., “The medullary dorsal horn: A site of action ofopioids in producing facial scratching in monkeys”, Anesthesiology, 79:548-554, 1993).

We have now surprisingly discovered that kappa agonist compounds, whichare substantially devoid of central nervous system effects, inpharmaceutically acceptable vehicles for systemic and topicalformulations possess anti-pruritic activity in addition toanti-hyperalgesic activity.

SUMMARY OF THE INVENTION

Compounds having kappa opioid agonist activity, compositions containingthem and method of using them for the treatment and/or prevention ofpruritus are provided.

In its compound aspect, the present invention provides a compound of theformulae I, II, IIA, III, IIIA, IV and IVA, or a pharmaceuticallyacceptable salt thereof.

The compounds of formula (I) have the following structure:

wherein

n=1-3, where n=1 is preferred R₁ and R₂ are independently ═CH₃;—(CH₂)_(m), where m=4-8, m=4 is most preferred; —CH₂CH(OH)(CH₂)₂—;CH₂CH(F)(CH₂)₂—; —(CH₂)₂O(CH₂)₂—; or —(CH₂)₂CH═CHCH₂—;

Ar=unsubstituted or mono- or di-substituted phenyl wherein saidsubstituents are selected from the group consisting of halogen, OCH₃,SO₂CH₃, CF₃, amino, alkyl and 3,4-dichloro; benzothiophenyl;benzofuranyl; naphthyl; diphenyl methyl; or 9-fluorene;

z is —P(O)(OBn)₂; —P(O)(OH)₂; —(CH₂)_(p)C(O)NHOH; —(CH₂)_(p)CO₂H;—SO₂CH₃; —SO₂NH₂; —CO(CH₂)_(p)CH(NH₂)(CO₂H); —COCH(NH₂)(CH₂)_(p)CO₂H;—CO₂CH₃; —CONH₂; —(CH₂)_(p)O(CH₂)_(p)CO₂H; —(CH₂)_(p)O(CH₂)_(p)CONHOH;—(CH₂)_(p)NHSO₂CH₃; —(CH₂)_(p)NHC(S)NHCH(CO₂H)(CH₂)_(p)CO₂H;—(CH₂)_(p)SO₃H; or

or Z is

 wherein

p=0-20;

R₃=—H or —Ac;

X₂=—CO₂H; —NHSO₂CH₃; NHP(O)(OBn)₂; NHP(O)(OH)₂; —OP(O)(OBn)₂; orOP(O)(OH)₂;

X and Y are independently —CH₂NHSO₂CH₃, —CH₂NHP(O)(OBn)₂,—CH₂NHP(O)(OH)₂, —CH₂OP(O)(OBn)₂, —CH₂OP(O)(OH)₂,—CH₂)_(q)O(CH₂)_(q)CO₂H, —(CH₂)_(q)O(CH₂)_(q)SO₃H,—(CH₂)_(p)O(CH₂)_(q)CHNHOH, —CH₂NHC(S)NHCH(CO₂H)(CH₂)_(q)CO₂H or

 wherein

r=1-20

R4=—H or —Ac

X₃=—CO₂H; —NHSO₂CH₃; —NHP(O)(OBn)₂; —NHP(O)(OH)₂; —OP(O)(OBn)₂; or—OP(O)(OH)₂.

The compounds of formula II have the following structure:

wherein

n=1-3, where n=1 is preferred

R₁ and R₂ are independently ═CH₃; —(CH₂)_(m), where m=4-8, m=4 is mostpreferred; —CH₂CH(OH)(CH₂)₂—; CH₂CH(F)(CH₂)₂—; —(CH₂)₂O(CH₂)₂—; or—(CH₂)₂CH═CHCH₂—;

Ar=unsubstituted or mono- or di-substituted phenyl wherein saidsubstituents are selected from the group consisting of halogen, OCH₃,SO₂CH₃, CF₃, amino, alkyl, and 3,4-dichloro; benzothiophenyl;benzofuranyl; naphthyl; diphenyl methyl; or 9-fluorene;

X₄ and X₅ are independently —OP(O)(OBn)₂; —OP(O)(OH); —CO₂H; —SO₃H;—SO₃H; —O(CH₂)_(n)CO₂H; —NHSO₂CH₃; —CONH(CH₂)_(s)CO₂H; or—SO₂NH(CH₂)_(s)CO₂H; wherein s=1-5

or X₄ and X₅ are independently

 wherein

t=1-20

R₅=—H or —Ac

X₆=—CO₂H; —NHSO₂CH₃; —NHP(O)(OBn)₂; —NHP(O)(OH)₂; —OP(O)(OBn)₂; or—OP(O)(OH)₂.

The compounds of formula IIA have the following structure:

wherein

n=1-3, where n=1 is preferred R₁ and R₂ are independently ═CH₃;—(CH₂)_(m), where m=4-8, m=4 is most preferred; —CH₂CH(OR)(CH₂)₂—wherein R is H, alkyl, acyl or aroyl; CH₂CH(F)(CH₂)₂—; —(CH₂)₂O(CH₂)₂—;or —(CH₂)₂CH═CHCH₂—;

Ar=mono- or di-substituted phenyl; wherein said substituents areselected from the group consisting of halogen, OCH₃, OH, SO₂CH₃, CF₃,NH₂, alkyl, CN, unsubstituted and substituted sulfamoyl groups;

Ar may also be substituted with —NH(CH₂)_(u)CO₂R′;—NH(CH₂)_(u)(CH═CH)_(u)(CH₂)CO₂R′;—NHCO(CH₂)_(u)(CH═CH)_(u)(CH₂)_(u)CO₂R′; —NHP(O)(OBn)₂; —NHP(O)(OR′)₂;—(CH₂)_(u)NHSO₂CH₃; —(CH₂)_(u)NHC(S)NHCH(CO₂R′)(CH₂)_(u)CO₂R′; —CONHOH;or —(CH₂)_(u)CONHOH;

 wherein

u=0-5;

R′=H or lower alkyl;

or Ar is

R₆=—H or —Ac

X₈=—CO₂H; —NHSO₂CH₃; —NHP(O)(OBn)₂; —NHP(O)(OH)₂; —OP(O)(OBn)₂; or—OP(O)(OH)₂;

R₇=—NH(CH₂)_(v)CO₂H; —NH(CH₂)_(v)CH(NH₂)(CO₂H); —NHCH(CO₂H)(CH₂)_(v)NH₂;—NH(CH₂)_(v)SO₃H; —NH(CH₂)_(v)PO₃H₂; —NH(CH₂)_(v)NHC(NH)NH₂; or—NHCH(CO₂H)(CH₂)_(v)CO₂H; and

v=1-20.

X₄ and X₅ are independently H; halogen; OH; OCH₃; CF₃; NO₂; NH₂; aminosubstituted with acyl, carbamate, alkyl or aryl sulfonates; COR′ whereR′ is OH, amide, alkoxy, aryloxy or heteroaryloxy.

Compounds of formula (IIA) have at least one chiral center and may existin more than one diastereoisomeric form. The invention includes withinits scope all enantiomers, and diastereosomers and the mixtures thereof.

The compounds of formula III have the following structure:

wherein

n=1-3, where n=1 is preferred R₁ and R₂ are independently ═CH₃;—(CH₂)_(m), where m=4-8, m=4 is most preferred; —CH₂CH(OH)(CH₂)₂—;CH₂CH(F)(CH₂)₂—; —(CH₂)₂O(CH₂)₂—; or —(CH₂)₂CH═CHCH₂—;

Ar=unsubstituted or mono- or di-substituted phenyl wherein saidsubstituents are selected from the group consisting of halogen, OCH₃,SO₂CH₃, CF₃, amino, alkyl, and 3,4-dichloro; benzothiophenyl;benzofuranyl; naphthyl; diphenyl methyl; or 9-fluorene;

X₇ is —NHSO₂CH₃; —NHP(O)(OBn)₂; —NHP(O)(OH)₂; —(CH₂)_(u)NHSO₂CH₃;—(CH₂)_(u)NHC(S)NHCH(CO₂H)(CH₂)_(u)CO₂H; —CONHOH; or —(CH₂)_(u)CONHOH;

 wherein

u=1-5

or X₇ is

R₆=—H or —Ac;

X₈=—CO₂H ; —NHSO₂CH₃; —NPO(O)(OBn)₂; —NHP(O)(OH)₂; —OP(O)(OBn)₂; or—OP(O)(OH)₂;

R₇=—NH(CH₂)_(v)CO₂H; —NH(CH₂)_(v)CH(HN₂)(CO₂H); —NHCH(CO₂H)(CH₂)_(v)NH₂;—NH(CH₂)_(v)SO₃H; —NH(CH₂)_(v)PO₃H₂; —NH(CH₂)_(v)NHC(NH)NH₂; or—NHCH(CO₂H)(CH₂)_(v)CO₂H; and

v=1-20.

The compounds of formula IIIA have the following structure:

wherein

n=1-3, where n=1 is preferred;

R₁ and R₂ are independently ═CH₃; —(CH₂)_(m), where m=4-8, m=4 is mostpreferred; —CH₂CH(OR)(CH₂)₂—, wherein R═H, alkyl, acyl or aroyl;CH₂CH(F)(CH₂)₂—; —(CH₂)₂O(CH₂)₂—; or —(CH₂)₂CH═CHCH₂;

Ar=mono- or di-substituted phenyl; wherein said substituents areselected from the group consisting of halogen, OCH₃, OH, SO₂CH₃, CF₃,NH2, alkyl, CN, unsubstituted and substituted sulfamoyl groups;

Ar may also be substituted with —NH(CH₂)_(u)CO₂R′;—NH(CH₂)_(u)(CH═CH)_(u)(CH₂)CO₂R′;—NHCO(CH₂)_(u)(CH═CH)_(u)(CH₂)_(u)CO₂R′; —NHP(O)(OBn)₂; —NHP(O)(OR′)₂;—(CH₂)_(u)NHSO₂CH₃; —(CH₂)_(u)NHC(S)NHCH(CO₂R′)(CH₂)_(u)CO₂R′; —CONHOH;or —(CH₂)₂CONHOH;

 wherein

u=0-5;

R′=H or lower alkyl;

or Ar is

R₆=—H or —Ac

X₈=—CO₂H; —NHSO₂CH₃; —NHP(O)(OBn)₂; —NHP(O)(OH)₂; —OP(O)(OBn)₂; or—OP(O)(OH)₂;

R₇=—NH(CH₂)_(v)CO₂H; —NH(CH₂)_(v)CH(NH₂)(CO₂H); —NHCH(CO₂H(CH₂)_(v)NH₂;—NH(CH₂)_(v)SO₃H; —NH(CH₂)_(v)PO₃H₂; —NH(CH₂)_(v)NHC(NH)NH₂; or—NHCH(CO₂H)(CH₂)_(v)CO₂H; and

v=1-20.

X₇ is H; halogen; OH; OCH₃; CF₃; NO₂; NH₂; amino substituted with acyl,carbamate, alkyl or aryl sulfonates; COR′ where R′ is OH, amide, alkoxy,aryloxy or heteroaryloxy.

Compounds of formula (IIIA) have at least one chiral center and mayexist in more than one diastereoisomeric form. The invention includeswithin its scope all enantiomers, and diastereosomers and the mixturesthereof.

The compounds of formula IV have the following structure:

wherein

n=1-3, where n=1 is preferred R₁ and R₂ are independently ═CH₃;—(CH₂)_(m), where m=4-8, m=4 is most preferred; —CH₂CH(OH)(CH₂)₂—;CH₂CH(F)(CH₂)₂—; —(CH₂)₂O(CH₂)₂—; or —(CH₂)₂CH═CHCH₂—;

R₃ and R₄ are independently H; OCH₃; alkyl; or C—O(CH₂)₂;

X₉=1-4 substituents selected from the groups consisting of —halogen;—CF₃; —OCH₃; —SO₂NH(CH₂)_(q)CO₂H; —CONH(CH₂)_(q)CO₂H; —NH₂; —NHSO₂CH₃;—NHP(O)(OBn)₂; —NHP(O)(OH)₂; —SO₂CH₃; —OP(O)(OBn)₂; —OP(O)(OH₂; —CO₂H;—O(CH₂)_(q)CO₂H; —O(CH₂)_(q)SO₃H , —O(CH₂)_(q)OPO₃H₂; wherein q=1-20.

or X₉ is

 wherein

t=1-20

R₅=—H or —Ac

X₆=—CO₂H; —NHSO₂CH₃; —NHP(O)(OBn)₂; —NHP(O)(OH)₂; —OP(O)(OBn)₂; or—OP(O)(OH)₂.

The compunds of formula IVA have the following structure:

wherein

n=1-3, where n=1 is preferred R₁ and R₂ are independently ═CH₃;—(CH₂)_(m), where m=4-8, m=4 is most preferred; —CH₂CH(OR)(CH₂)₂—;wherein R=H, alkyl, acyl, or aroyl; CH₂CH(F)(CH₂)₂—; —(CH₂)₂O(CH₂)₂—; or—(CH₂)CH═CHCH₂—;

R₃ and R₄ are independently H; OCH₃; alkyl; or —O(CH₂)₂;

X₉=1-4 substituents selected from the groups consisting of —halogen;—CF₃; OH, —OCH₃; —SO₂NH(CH₂)_(q)CH₃; —NH(CH₂)_(q)COR′;—NH(CH₂)_(q)(CH═CH)_(q)(CH₂)_(q)CO₂R′;—NH(CH)_(q)(CH≡CH)_(q)(CH)_(q)CO₂R;—NHCO(CH₂)_(q)(CH═CH)_(q)(CH₂)_(q)CO₂R; and—NHCO(CH)_(q)(CH═CH)_(q)(CH)_(q)CO₂R′

 wherein

q=0-20

R′=OH, lower alkyl, aryl ester or aryl amide.

Compounds of formula (IVA) have at least one chiral center and may existin more than one diastereoisomeric form. The invention includes withinits scope all enantiomers, and diastereosomers and the mixtures thereof

The meaning of the terms used in the specification and the claims,unless otherwise denoted, are as follows.

The term “alkyl” as used herein alone or as part of another group,denotes optionally substituted, straight and branched chain saturatedhydrocarbon groups, preferably having 1 to 12 carbons in the normalchain, most preferably lower alkyl groups. Exemplary unsubstitutedgroups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl,isobutyl, pentyl, hexyl, isohexyl, 4,4-dimethylpentyl, octyl,2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl and the like.Exemplary substituents include one or more of the following groups:halo, alkoxy, arylalkyloxy (e.g., benzyloxy), alkylthio, alkenyl,alkynyl, aryl, cycloalkyl, cycloalkenyl, hydroxy, carboxyl (—COOH),amino, alkylamino, dialkylamino, formyl, alkylcarbonyloxy,alkylcarbonyl, heterocyclo, aryloxy or thiol (—SH). Preferred alkylgroups are unsubstituted alkyl, haloalkyl, arylalkyl, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, alkoxyalkyl, aryloxyalkyl,hydroxyalkyl and alkoxyalkyl groups.

The term “lower alkyl” as used herein denotes such optionallysubstituted groups as described above for alkyl having 1 to 4 carbonatoms in the normal chain.

The terms “ar” or “aryl” as used herein or as part of another group,denote optionally substituted, homocyclic aromatic groups, preferablycontaining 1 or 2 rings and 6 to 12 ring carbons. Exemplaryunsubstituted groups include phenyl, biphenyl and naphthyl. Exemplarysubstituents include one or more, preferably three or fewer, nitrogroups, alkyl groups as described above, and/or one or more groupsdescribed above as alkyl substituents. Preferred aryl groups areunsubstituted aryl and hydroxyaryl.

The terms “heterocyclo” or “heterocyclic” as used herein alone or aspart of another group, denote optionally substituted fully saturated orunsaturated, aromatic or non-aromatic cyclic groups having at least oneheteroatom in at least one ring, preferably monocyclic or bicyclicgroups having 5 or 6 atoms in each ring. The heterocyclo group may, forexample, have 1 or 2 oxygen atoms, 1 or 2 sulfur atoms, and/or 1 to 4nitrogen atoms in the ring. Each heterocyclo group may be bonded throughany carbon or heteroatom off the ring system n Preferred groups includethose of the following formula, which may be bonded through any atom ofthe ring system:

wherein r is 0 or 1 and T is —O—, —S—, —N—R⁸ or —CH—R⁸ where R⁸ ishydrogen, alkyl, aryl or arylalkyl. Exemplary heterocyclo groups includethe following: thienyl, furyl, pyrrolyl, pyridyl, imidazolylpyrrolidinyl, piperidinyl, azepinyl indolyl, isoindolyl, quinolinyl,isoquinolinyl benzothiazolyl, benzoxazolyl, benzimidazolyl, morpholinyl,piperazinyl 4-alkylpiperazinyl 4-alkylpiperidinyl, 3-alkpyrrolidinyl,oxazolyl pyrazolyl thiophenyl, pyridazinyl, thiazolyl triazoyl,pyrimidinyl, 1,4-dioxanyl, benzoxadiazolyl, and benzofurazanyl.Exemplary substituents include one or more alkyl groups as describedabove and/or one or more groups described above as alkyl substituents.

The terms “halogen” or “halo” as used herein alone or as part of anothergroup, denote chlorine, bromine, fluorine and iodine.

The term “acyl”, as used herein alone or as part of another group,denotes the moiety formed by removal of the hydroxyl group from thegroup —COOH of an organic carboxylic acid. Exemplary groups includealkylcarbonyl arylcarbonyl, or carbocyclo- or heterocyclocarbonyl. Theterm “acyloxy”, as used herein alone or as part of another group denotesan acyl group as described above bonded through an oxygen linkage (—O—).

DETAILED DESCRIPTION OF THE INVENTION

Peripherally-acting κ agonists can be prepared by the attachment ofpolar groups to non-peptide κ opioid receptor selective agonists, suchas the arylacetamides. In designing the peripherally-acting ligands, theintroduction of the polar groups may result in either retention orenhancement of antinociceptive potency and selectivity and also mayincrease the polarity of the ligand sufficient to reduce or eliminateCNS penetration across the blood-brain barrier (BBB). Thus, the identityand the positioning of the polar group(s) are important.

Using the prototypic arylacetamide, U50,488, as an example, thearylacetamide pharmacophore can be divided into three regions: thearomatic region, the central region, and the amine region. All threeregions represent potential positions for the attachment of polargroups.

Compounds of formula (I) of the present invention are made as follows.

A series of novel compounds were made based on the class ofarylacetamides reported by Glaxo (J. Med. Chem. 1993, 36, 2075).Specifcally, compound 1 can be deprotected to yield intermediate 2,which can be derivatized by the attachment of a variety of polar groups(Scheme 1).

The 3′-substituted series can be prepared via Scheme 2. The reduction ofthe Schiff base intermediate formed during the cyclization to 6 isexpected to be stereoselective due to the directing effect of theneighboring hydroxymethyl group. Both intermediates 11 and 12 can bederivatized to confer peripheral selectivity.

The 5′-substituted series can be prepared via Schemes 3 and 4. Startingfrom N-t-Boc-O-MEM-D-serine, the 5′-(S) series can be prepared, andstarting from from N-t-Boc-O-MEM-L-serine allows the preparation of the5′-(R) series.

wherein Ar, R₁, R₂, and n are defined in formula I.

wherein Ar, R₁, R₂, and n are as defined in formula I.

wherein Ar, R₁, R₂, and n are as defined in formula I.

wherein Ar, R₁, R₂, and n are as defined in formula I.

Using Schemes 1-4 the following example compounds are made.

Intermediate 3 can be treated with t-butyl bromoacetate and deprotectedto produce{4-[1-(3,4-Dichlorophenyl)acetyl-2R-(1-pyrrolidinyl)-methyl]piperazinyl}aceticacid (26).

Intermediate 3 can be reacted with methane sulfonyl chloride to produce[1-(3,4-Dichlorophenyl)acetyl-4-methanesulfonyl-2R-(1-pyrrolidinyl)methyl]piperazine(27).

Intermediate 3 can be coupled to N-t-Boc-L-aspartic acid-b-benzyl esterand deprotected to produce [4-S-Asparticacid-a-amido-1-(3,4-dichlorophenyl)acetyl-2R-(1-pyrrolidinyl)methyl]piperazine(28).

Intermediate 11 can be treated with t-butyl bromoacetate and deprotectedto produce Methyl-[2R-(O-2-aceticacid)hydroxymethyl-4-(3,4-dichlorophenyl)acetyl-3R-(1-pyrrolidinyl)methyl]-1-piperazinecarboxylate(29).

Intermediate 11 can be coupled to to N-t-Boc-L-aspartic acid-b-benzylester and deprotected to produce Methyl-[2R-(O-S-asparticacid-a-acetyl)hydroxymethyl-4-(3,4-dichlorophenyl)acetyl-3R-(1-pyrrolidinyl)methyl]-1-piperazinecarboxylate(30).

Intermediate 12 can be treated with methanesulfonyl chloride to produceMethyl-[4-(3,4-dichlorophenyl)acetyl-2R-N-methanesulfonamido)aminomethyl-3R-(1-pyrrolidinyl)methyl]-1-piperazinecarboxylate(31).

Intermediate 12 can be coupled to 2S-isothiocyanato-succinicacid-dibenzyl ester and deprotected to yieldMethyl-{4-[3,4-dichlorophenyl]acetyl-3R-[1-pyrrolidinyl]methyl-2R-[N-(succinicacid-2S-thioureido)]aminomethyl}-1-piperazinecarboxylate (32).

Intermediate 21 can be treated with t-butyl bromoacetate and deprotectedto produce Methyl-[2S-(O-2-aceticacid)hydroxymethyl-4-(3,4-dichlorophenyl)acetyl-5R-(1-pyrrolidinyl)methyl]-1-piperazinecarboxylate(33).

Intermediate 21 can be coupled to to N-t-Boc-L-aspartic acid-b-benzylester and deprotected to produce Methyl-[2S-(O-S-asparticacid-a-acetyl)hydroxymethyl-4-(3,4-dichlorophenyl)acetyl-5R-(1-pyrrolidinyl)methyl]-1-piperazinecarboxylate(34).

Intermediate 22 can be treated with methanesulfonyl chloride to produceMethyl-[4-(3,4-dichlorophenyl)acetyl-2S-(N-methanesulfonamido)aminomethyl-5R-(1-pyrrolidinyl)methyl]-1-piperazinecarboxylate(35).

Intermediate 22 can be coupled to 2S-isothiocyanato-succinicacid-dibenzyl ester and deprotected to yieldMethyl-{4-[3,4-dichlorophenyl]acetyl-5R-[1-pyrrolidinyl]methyl-2S-[N-(succinicacid-2S-thioureido)]aminomethyl}-1-piperazinecarboxylate (36).

The 2R isomers of 33-34 and 35-36 can be prepared from intermediates 24and 25, respectively to produce

Methyl-[2R-(O-2-aceticacid)hydroxymethyl-4-(3,4-dichlorophenyl)acetyl-5R-(1-pyrrolidinyl)methyl]-1-piperazinecarboxylate(37).

Methyl-[2R-(O-S-asparticacid-a-acetyl)hydroxymethyl-4-(3,4-dichlorophenyl)acetyl-5R-(1-pyrrolidinyl)methyl]-1-piperazinecarboxylate(38).

Methyl-[4-(3,4-dichlorophenyl)acetyl-2R-(N-methanesulfonamido)aminomethyl-5R-(1-pyrrolidinyl)methyl]-1-piperazinecarboxylate(39).

Methyl-{4-[3,4-dichlorophenyl]acetyl-5R-[1-pyrrolidinyl]methyl-2R-[N-(succinicacid-2S-thioureido)]aminomethyl}-1-piperazinecarboxylate (40).

The corresponding structural formulas are shown hereunder.

Compounds of formula II of the present invention are made byperipheralization by substitutions of the benzo portion of thetetrahydronaphthyl ring of DuPont series of compounds with polar groups.

Starting material or precursors of the starting material arecommercially available and thus allows regiospecific substitutions ofthe tetrahydronaphthyl ring (Scheme 5). While 5-hydroxytetralone,6-hydroxytetralone, 7-hydroxytetralone, and 7-aminotetralone derivativesare readily available, 5-aminotetralone could be prepared from5-hydroxytetralone (J. Org. Chem. 1972, 37, 3570).

The tetralone derivatives can be converted to dihydronaphthylderivatives and subjected to chemistry similar to that employed in thepreparation of U50,488 derivatives. The resulting compounds are racemicmixtures that can be derivatized to confer peripheral selectivity. Ifnecessary, the final compounds or one of the intermediates can beresolved to test both enantiomers.

wherein R₁, R₂, and n are as defined in formula I.

Following the procedure shown in Schemes 5-7, the following examplecompounds are prepared.

Intermediate (±)-64 can be treated with t-butyl bromoacetate anddeprotected to produce(±)-2-(3,4-dichlorophenyl)-N-methyl-N-1-[1,2,3,4-tetrahydro-5-(O-2-aceticacid)-hydroxy-2-(1-pyrrolidinyl)naphthyl]acetamide (72).

Intermediate (±)-65 can be treated with t-butyl bromoacetate anddeprotected to produce(±)-2-(3,4-dichlorophenyl)-N-methyl-N-1-[1,2,3,4-tetrahydro-7-(O-2-aceticacid)-hydroxy-2-(1-pyrrolidinyl)naphthyl]acetamide (73).

Intermediate (±)-66 can be treated with methanesulfonyl chloride toproduce(±)-2-(3,4-dichlorophenyl)-N-methyl-N-1-[1,2,3,4-tetrahydro-7-(N-methanesulfonamido)-amino-2-(1-pyrrolidinyl)naphthyl]acetamide(74).

Intermediate (±)-67 can be treated with methanesulfonyl chloride toproduce(±)-2-3,4-dichlorophenyl)-N-methyl-N-1-[1,2,3,4-tetrahydro-5-(N-methanesulfonamido)-amino-2-(1-pyrrolidinyl)naphthyl]acetamide(75).

Intermediate (±)-68 can be treated with glycine benzyl ester anddeprotected to produce(±)-2-(3,4-dichlorophenyl)-N-methyl-N-1-[1,2,3,4-tetrahydro-5-(N-2-aceticacid)-carboxamido-2-(1-pyrrolidinyl)naphthyl]acetamide (76).

Intermediate (±)-69 can be treated with glycine benzyl ester anddeprotected to produce(±)-2-(3,4dichlorophenyl)-N-methyl-N-1-[1,2,3,4-tetrahydro-5-(N-2-aceticacid)-sulfonamido-2-(1-pyrrolidinyl)naphthyl]acetamide (77).

Intermediate (±)-70 can be treated with glycine benzyl ester anddeprotected to produce(±)-2-(3,4-dichlorophenyl)-N-methyl-N-1-[1,2,3,4-tetrahydro-7-(N-2-aceticacid)-carboxamido-2-(1-pyrrolidinyl)naphthyl]acetamide (78).

Intermediate (±)-71 can be treated with glycine benzyl ester anddeprotected to produce(±)-2-(3,4-dichlorophenyl)-N-methyl-N-1-[1,2,3,4-tetrahydro-7-(N-2-aceticacid)-sulfonamido-2-(1-pyrrolidinyl)naphthyl]acetamide (79).

(±)-72, X₅=—H, X₄=OCH₂CO₂H

(±)-73, X₅=—OCH₂CO₂H, X₄=—H

(±)-74, X₅=—NHSO₂Me, X₄=—H

(±)-75, X₅=—H, X₄=—NHSO₂Me

(±)-76, X₅=—H, X₄=—CONHCH₂CO₂H

(±)-77, X₅=—H, X₄=—SO₂NHCH₂CO₂H

(±)-78, X₅=—CONHCH₂CO₂H, X₂4=—H

(±)-79, X₅=—SO₂NHCH₂CO₂H, X₄=—H

The compounds of formula III of the present invention are prepared bysubstituting the central phenyl ring with polar groups.

wherein Ar, R₁, R₂, X₇, and n are defined as in formula III.

Compound 80 and analogues undergo a variety of diazonium-involvingreactions for the attachment of polar groups (Scheme 7).

Using the procedure shown in Scheme 7, the following compounds are made.

Intermediate 81 can be treated with dibenzyl phosphoryl chloridefollowed by deprotection to produce2-3,4dichlorophenyl)-N-methyl-N-{1-3-(O-phosphoryl)hydroxyphenyl-2-(1-pyrrolidinyl)ethyl}acetamide(87).

Intermediate 85 can be coupled to methanesulfonyl chloride to produce2-(3,4-dichlorophenyl)-N-methyl-N-{1-[3-(N-methanesulfonamido)aminomethyl]phenyl-2-(1-pyrrolidinyl)ethyl}acetamide(88).

Intermediate 85 can be coupled to 2S-isothiocyanato succinic acid anddeprotected to produce2-(3,4-dichlorophenyl)-N-methyl-N-{1-[3-(N-succinicacid-2S-thioureido)aminomethyl]phenyl-2-(1-pyrrolidinyl)ethyl}acetamide(89).

Intermediate 80 can be treated with dibenzyl phosphoryl chloridefollowed by deprotection to produce2-(3,4dichlorophenyl)-N-methyl-N-{1-3-(N-phosphoramido)aminophenyl-2-(1-pyrrolidinyl)ethyl}acetamide(90).

87, R=—OPO₃H₂

88, R=—CH₂NHSO₂Me

89, R=(S) —CH₂NHC(S)NHCH(CO₂H)CH₂CO₂H

90, R=—NHPO₃H₂

The compounds of formula IV may be prepared by Scheme 8.

wherein R₁, R₂, R₃, and R₄ are defined in formulas III and IV.

The diamino intermediate 91 (J. Med. Chem. 1990, 33, 286) can be coupledto different regioisomers of nitrophenylacetic acid, which are allcommercially available. Reduction of the nitro group provides an aminogroup for the attachment of polar groups. Alternatively, the aminointermediates 95-97 readily undergo diazonium chemistry that convertsthe amino groups to carboxyl and sulfonyl chloride groups. This allowsthe polar groups to be attached via different linkers.

Following the procedure in Scheme 8, the following compounds are made.

Intermediate 96 can be treated with methanesulfonyl chloride to produce(−)-(5a,7a,8β)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro-[4,5]dec-8-yl]-3-(N-methanesulfonamido)aminophenylacetamide(104).

Intermediate 98 can be coupled to glycine benzyl ester and deprotectedto yield(−)-(5a,7a,8β)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro-[4,5]dec-8-yl]-3-(N-acid)sulfonamidophenylacetamide(105).

Intermediate 99 can be coupled to glycine benzyl ester and deprotectedto yield(−)-(5a,7a,8β)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro-[4,5]dec-8-yl]-3-(N-2-aceticacid)carboxamidophenylacetamide (106).

104, X=NHSO₂CH₃,

105, X=SO₂NHCH₂CO₂H

106, X—CONHCH₂CO₂H

Compounds of the above formulas may have one or more asymmetric carbonatoms. Pure sterochemically isomeric forms of the above compounds may beobtained, and diastereoisomers isolated by physical separation methods,including, but not limited to crystallization and chromatographicmethods. Cis and trans diasteriomeric racemates may be further resolvedinto their isomers. If separated, active isomers may be identified bytheir activity. Such purification is not, however, necessary forpreparation of the compositions or practice of the methods herein.

As used herein, the compounds provided herein also includepharmaceutically acceptable salts, acids and esters thereof,stereoisomers, and also metabolites or prodrugs thereof that possessactivity as analgesics but do not cause substantial CNS effects whenadministered or applied. Metabolites include any compound that isproduced upon administration of the compound and metabolism thereof

More detailed preparations of the compounds of the present inventionfollow.

Compounds of Formula I

Preparatory for the compounds of formula I, the following intermediateswere prepared.

N-Benzyl-D-serine(1)¹

To a mixture of D-serine (25.0 g, 0.237 mol) and 200 mL anhydrousmethanol was added sodium cyanoborohydride (11.95 g, 0.190 mol), whilemaintaining the temperature at 0° C. with an ice bath Then, benzaldehyde(26.5 mL, 0.261 mol) was added to the reaction flask, dropwise, at 30°C. The mixture was stirred for 60 Hr. at room temperature. Then, themixture was filtered and rinsed with methanol (50 mL). The white solidwas dried in a vacuum oven at 40° C. and 10 mmHg over 2 nights: 24.5 g.The filtrate was retained and the solvent was evaporated. This oil waspassed through a silica gel column (10% MeOH/CH₂Cl₂) and 3.4 g of thedesired compound was isolated. The total amount of the product was 27.9g (60.0% yield). ¹H NMR (DMSO-d₆) δ3.25 (m, 1H, CH), 3.85 (m, 2H, CH₂),4.11 (d, 2H, benzylic CH₂), 7.45-7.53 (n, 5H, ArH).

Ref.

(1) Ohfune, Y.; Kurokawa, N.; Higuichi N.; Saito, M.; Hashimoto, M.;Tanaka, T. An efficient one-step reductive N-monoalkyation of α-aminoacids. Chemistry Letters. 1984, 441-444.

N-Benzyl-D-serine methyl ester(2)

Hydrogen chloride (gas) was bubbled into anhydrous methanol for 10minutes. Then, the solution was allowed to cool to room temperature.Then, N-benzyl-D-serine (24.6 gm, 0.126 mol) was added to the reactionflask and refluxed over night under dry nitrogen. Then, the solvent wasevaporated and dissolved in dichloromethane (200 mL), and washed with asaturated solution of sodium bicarbonate. The dichloromethane layer wasdried with magnesium sulfate and the solvent was evaporated. (23 gm,87.2% yield). ¹H NMR (CDCl₃) δ3.41 (d, 1H, CH), 3.52-3.80 (dd, 2H,benzylic), 3.69 (s, 3H, OMe), 7.27 (s, 5H, ArH).

N-[(1,1-Dimethylethoxy)carbonyl-D-Ser-(O-Bzl)-N-benzyl-D-Ser-OMe (3)

To a solution of N-boc-D-serine-(O-bzl)OH (15 g, 50.76 mmol) inanhydryous dichloromethane (200 mL) was added HOBt (7.54 g, 55.8 mmol)at 0° C. under dry nitrogen. Then, DCC (11.5 g, 55.7 mmol) indichloromethane (100 mL) was added dropwise to the reaction flask. Then,this mixture was stirred for 1 Hr. Then, N-benzyl-D-serine-OMe (10 g,47.8 mmol) in dichloromethane (100 mL) was added dropwise to thereaction flask. Then, stirred for 4 days. Then, filtered and rinsed withdichloromethane (100 ml). The white precipitate was DCU and HOBt. Thefiltrate was evaporated and re-dissolved in ethyl acetate (100 mL).Then, this was allowed to recipitate, overnight—more DCU. This wasfiltered and rinsed with ethyl acetate. Then, this was isolated on asilica gel column (20% ethyl acetate/hexanes): an oil-17.3 g, 74.3%yield. ¹H NMR (CDCl₃) δ1.43 (s, 9H t-Bu), 3.54 (t, 1H, OH), 3.72 (s, 3H,OMe), 3.75 (dd, 2H, CH₂) 3.79 (dd, 2H, CH₂), 4.41 (d, 2H, CH₂ benzylic),4.43 (d, 2H, CH₂ benzylic), 7.27-7.30(m, 10H, ArH).

(2R,5R)-2-((Benzyloxy)methyl)-5-(Hydroxymethyl)-4-(phenylmethyl)-3,6-piperazinedione(4)²

Into anhydrous chloroform (300 mL) was bubbled hydrogen chloride (gas).Then, the dipeptide (3) (13.5 g, 27.7 mmol) in chloroform (100 ml) wasadded to the reaction flask. The flask was stoppered and stirred for 64Hr. Then, a saturated solution (100 ml) of sodium bicarbonate was addedand stirred vigorously for 48 Hr. The cyclization was completed at thispoint. The organic layer was separated from the aqueous layer in a 1 Lseparatory funnel. The product was isolated from a silica gel column,eluting with dichloromethane-methanol-0.88 ammonia (96:2:2) to give (4)as an amorphous solid (6.0 g, 61.1% yield). ¹H NMR (CDCl₃) δ3.72-3.96(m, 7H), 3.97-5.24 (dd, 2H, CH₂ benzylic), 4.45 (dd, 2H, CH₂ benzylic),7.15-7.30 (m, 10H, ArH); MS (FAB) m/e 355 (MH⁺).

Ref.

(2) Williams, T. M.; Ciccarone, T. M.; MacTough, S. C. and et al.2-Substituted piperazines as constrained amino acids. J. Med. Chem.1996, 39, 1345-1348.

(2S,5S)-2-((Benzyloxy)methyl)-4-(phenylmethyl)-5-piperazinemethanol(5)

A suspension of lithium aluminum hydride (0.9 g, 23.7 mmol) in anhydroustetrahydrofuran (40 mL) was treated with a solution of piperazinedione 4(2.1 g, 5.92 mmol) in anhydrous tetrahydrofuran (200 mL). The reactionmixture was heated at reflux for 24 Hr and then, stirred at roomtemperature for 12 Hr. Water (10 ml) was added followed by aqueoussodium hydroxide (1N, 10 mL) and water (10 mL). The mixture wasfiltered, and the filtrate was evaporated to give 5 (1.67 g, 86.4%yield) as a viscous oil. ¹H NMR (CDCl₃) δ2.58 (dd, 2H, CH₂), 2.61 (t,1H, OH), 3.10 (dd, 2H, CH₂), 3.25 (dd, 2H, CH₂), 3.50 (dd, 2H, CH₂),3.74(s, 2H, CH₂), 4.41 (dd, 2H, CH₂ benzylic), 7.20-7.30 (m, 10H, ArH).

(2S,5S)-Methyl2-[Benzyloxy)methyl]-5-(hydroxymethyl)-4-(phenylmethyl)-1-piperazinecarboxylate (6)³

A solution of 5 (1.67 g, 5.11 mmol.) in acetonitrile (20 mL) was treatedwith a solution of methyl chloroformate (0.532 g, 5.63 mmol) inacetonitrile (10 mL) at 0° C. The mixture was stirred at ambienttemperature for 30 min., and then aqueous sodium carbonate solution (15mL) was added. The organic solvent was removed, and the aqueous residuewas extracted with chloroform (3×10 mL). The combined organic extractswere washed with aqueous sodium carbonate solution (10 mL), dried, andevaporated to give 6 (1.52 g, 77.3% yield) as an oil. ¹H NMR (CDCl₃)δ2.54 (dd, 2H, CH₂), 2.45 (t, 1H, OH), 2.72 (dd, 2H, CH₂), 3.51 (dd, 2H,CH₂), 3.67 (dd, 2H, CH₂), 3.69 (s, 3H, OMe), 3.81 (dd, 2H, CH₂), 4.44(dd, 2H, CH₂ benzylic), 7.17-7.31 (10H, ArH).

(2S,5S)-Methyl2-[(Benzyloxy)methyl]-5-[(1-pyrrolidinyl)methyl]-4-phenylmethyl-1-piperazinecarboxylate(7)³

A solution of oxalyl chloride (0.545 mL, 6.24 mmol) in dichloromethane(10 mL) at −65° C. was treated with a solution of dimethyl sulfoxide(1.14 mL, 16.0 mmol) in dichloromethane (5 ml) maintaining the reactiontemperature below −65° C. The mixture was stirred at −70° C. for 10 min,and then a solution of the piperazinemethanol (6: 2 g, 5.19 mmol) indichloromethane (20 mL) was added at such a rate that the reactiontemperature was maintained below −65° C. The reaction mixture wasstirred at −65° C. for 3 Hr, and a solution of N-methylmorpholine (1.42mL, 12.91 mmol) in dichloromethane (5 mL) was added. The mixture wasstirred at −20° C. for 45 min and then washed with ice-cold hydrochloricacid (0.01 N, 100 mL and 50 ml), dried, evaporated, and placed on a highvacuum pump overnight. The residue was dissolved in methanol (10 mL) andwas added to a solution of pyrrolidine (0.91 mL, 10.94 mmol) in methanol(10 mL) at −10° C., which had been adjusted pH 6.0 by the addition ofmethanolic hydrogen chloride. Sodium cyanoborohydride (0.67 g, 10.66mmol) and 4-Å molecular sieves (0.66 g) were added, and the mixture wasstirred at ambient temperature for 18 Hr. The mixture was filtered, andthe filtrate was evaporated to dryness. The residue was dissolved inaqueous sodium carbonate (1M, 25 mL,) and extracted with dichloromethane(2×50 mL). The product was isolated from a silica gel column, elutingwith dichloromethane-methanol (98:2) to give (7:1.0 g, 23.0% yield). ¹HNMR (CDCl₃) δ1.75 (m, 4H, CH₂CH₂), 2.46 (m, 3H), 2.48 (m, 4H, CH₂CH₂),2.55 (dd, 2H, CH₂), 2.70-2.85 (m, 3H), 3.41 (dd, 2H, CH₂), 3.69 (s, 3H,OMe), 4.10 (m, 1H), 4.20 (m, 1H), 4.41 (dd, 2H, CH₂ benzylic), 7.10-7.31(m, 10H, ArH); MS (FAB) m/e 438 (MH⁺).

(3) Naylor, A.; Judd, D. B.; Lloyd, J. E.; Scopes, D. I. C.; Hayes, A.G.; Birch, P. J. A potent new class of k-Receptor agonist: 4-subtituted1-(arylacetyl)-2-[(dialkylamino)methyl]piperazines. J. Med. Chem. 1993,36, 2075-2083.

(2S,5S)-Methyl 2-(Hydroxymethyl)-5-[(1-pyrrolidinyl)methyl-1-piperazinecarboxylate(8)

A solution of 7 (0.25 g, 0.571 mmol) in ethanol (200 mL) washydrogenated over 10% palladium on carbon (Degussa type E101 NE/W) at 50psi for 7 days. Then, filtered through celite and filtrate wasevaporated. (0.13 g, 0.5 mmol: 87% yield).

(2S,5S)-Methyl4-[(3,4-Dichlorophenyl)acetyl]-2-(hydroxy)methyl-5-[(1-pyrrolidinyl)methyl]-1-piperazinecarboxylate(9)

To a solution of 1,1′-carbonyldiimiazole (0.20 g, 1.26 mmol) indichloromethane (10 mL) was added portionwise 3,4-dichlorophenylaceticacid (0.25 g, 1.26 in mmol) and the resulting solution stirred undernitrogen for 1 Hr, at room temperature. A solution of 8 (0.13 g, 0.5mmol) in dichloromethane (10 mL) was added and the mixture at roomtemperature for 18 Hr. The reaction mixture was washed with sodiumcarbonate solution (2 N, 2×10 mL), dried, and evaporated to give aviscous oil. This material was dissolved in a mixture of tetrahydrofuran(5 mL) and water (5 mL) and treated with lithium hydroxide (42 mg, 1.0mmol). The reaction mixture was removed, and the aqueous residue wasextracted with dichloromethane (3×10 mL). The combined organic extractswere dried and evaporated to give a colorless gum which was purified byflash column chromatography on silica gel, eluting with ethylacetate-methanol (40:1) to give 9 (155 mg, 70%) as a colorless foam.

Utilizing the above-denoted intermediates, the following compounds wereprepared.

CHIRAL COMPOUNDS

EXAMPLE 1(R)-4-(Phenylmethyl)-1-[(3,4-dichlorophenyl)acetyl]-2-[(1-pyrrolidinyl)methyl]piperazinehydrochloride [(R)-1 HCl] ADL-01-0143-6

The compound (R)-1 HCl was prepared following the literature procedures³in 54% yield; mp 168-170° C.; ¹H NMR (free base, 200 MHz, CDCl₃) δ1.65(4H, m), 1.95-3.00 (6H, m), 3.10-3.80 (9H, m), 4.35 (1H, m), 4.70 (1H,m), 7.00 (1H, m), 7.30 (7H, m); MS (FAB) 448 (M+H)⁺; Anal. Calcd forC₂₄H₂₉Cl₂N₃O.2HCl.H₂O: C, 53.64; H, 6.19; N, 7.82. Found: C, 53.69; H,5.88; N, 7.49.

EXAMPLE 2(R)-1-[(3,4-Dichlorophenyl)acetyl]-2-[(1-pyrrolidinyl)methyl]piperazinehydrochloride [(R)-2HCl] ADL-01-0047-9

The compound was prepared by the catalytic hydrogenation of (R)-1 HClfollowing the procedure described in the above reference. The productwas isolated as a free base as clear oil in 81% yield and thedihydrochloride salt was prepared from 1M etherial HCl; ¹H NMR (freebase, 200 MHz, CDCl₃) δ1.67 (4H, m), 1.95-3.10 (6H, m), 3.10-3.80 (7H,m), 4.30 (1H, m), 4.65 (1H, m), 7.05 (1H, m), 7.35 (3H, m); MS (FAB) 356(M+H)⁺.

EXAMPLE 3(R)-4-Methanesulfonyl-1-[(3,4-dichlorophenyl)acetyl]-2-[(1-pyrrolidinyl)methyl]-piperazinehydrochloride [(R)-3a HCl] ADL-01-0039-6

To the solution of (R)-2 (712 mg, 2 mmol in 10 ml CH₂Cl₂),methanesulfonyl chloride (573 mg, 5 mmol) and pyridine (1 ml) were addedat 0° C., stirred overnight at that temperature, the solution was washedwith aq. 5% K₂CO₃ solution, extracted with dichloromethane, dried andevaporated solvent to give crude oil. This material was purified byflash column chromatography on silica gel, eluting withdichloromethane-methanol-ammonia (100:5:1), to give the free base, whichwas dissolved into 2 ml of dichloromethane and HCl (3 ml, 1 M in Et₂O)was added to afford a white salt (R)-3a HCl (600 mg, 69%): mp 130-132°C.; ¹H NMR (free base, 200 MHz CDCl₃) δ1.61-1.85 (4H, m), 2.38-2.65 (6H,m), 2.72 (3H, s), 2.80-3.06 (2H, m), 3.15-3.36 (1H, m), 3.50-3.96 (4H,m), 4.48-4.93 (1H, m), 7.00-7.10 (1H, m), 7.25-7.40 (2H, m); MS (FAB)434 (M+H)⁺; Anal. Calcd for C₁₈H₂₅Cl₂N₃O₃S.HCl.0.5CH₃OH.: C, 45.64; H,5.59; N, 8.63. Found: C, 45.69; H, 5.58; N, 8.73.

EXAMPLE 4(R)-4-t-Butyl-acetyl-1-[(3,4-dichlorophenyl)acetyl]-2-[(1-pyrrolidinyl)methyl]-piperazine[(R)-3b] ADL-01-0040-4

To the solution of (R)-2 (356 mg, 1 mmol in 10 ml acetone), t-butylbromoacetate (234 mg, 1.2 mmol) and K₂CO₃ (207 mg, 1.5 mmol) were addedat 0° C., stirred overnight at that temperature, the solution was washedwith aq. 5% K₂CO₃ solution, extracted with dichloromethane, dried andevaporated solvent to give crude oil. This material was purified byflash column chromatography on silica gel, eluting withdichloromethane-methanol-ammonia (100:5:1), to give (R)-3b (329 mg,70%): ¹H NMR (free base, 200 MHz, CDCl₃) δ1.36 (9H, s), 1.91-2.37 (7H,m), 2.65-3.13 (7H, m), 3.58-4.20 (6H, m), 5.00 (1H, m), 7.12-7.21 (2H,m), 7.40 (1H, m). The compound was used directly into the followingreaction.

EXAMPLE 5(R)4-[(3,4-dichlorophenyl)acetyl]-3-[(1-pyrrolidinyl)methyl]-1-piperazineaceticacid dihydrochloride [(R)-3c 2HCl] ADL-01-0042-0

Compound (R)-3b (329 mg, 0.7 mmol) was dissolved into 5 ml THF/Et₂O(1:1), and HCl (5 ml, 1 M in Et₂O) was added, kept 12 hrs to afford awhite salt (R)-3c HCl (275 mg, 61%): mp 190° C. (d). ¹H NMR (free base,200 MHz, CDCl₃) δ1.85-2.20 (4H, m), 2.95-4.41 (17H, m), 5.18-5.35 (1H,m), 7.30-7.45 (1H, m), 7.56-7.72 (2H, m); MS (FAB) 414 (M+H)⁺; Anal.Calcd for C₁₉H₂₅Cl₂N₃O₃.2 HCl.0.5 H2O.: C, 45.16; H, 5.78; N, 8.32.Found: C, 44.91; H, 5.88; N, 8.56.

EXAMPLE 6 (R)-4-N-t-Boc-D-aspartic acid-β-benzylester-1-[(3,4-dichlorophenyl)acetyl]-2-[(1-pyrrolidinyl)methyl]-piperazine[(R)-3d] ADL-01-0048-7

To the solution of N-t-Boc-D-aspartic acid-β-benzyl ester (646 mg, 2mmol) and HOBt (270 mg, 2 mmol in 10 ml CH₂Cl₂), DCC (413 mg, 2 mmol)was added at 0° C., stirred 1h at that temperature, (R)-2 (356 mg, 1mmol in 10 ml CH₂Cl₂) was added, stirred 24 hrs at room temperature, thesolution was washed with aq. 5% K₂CO₃ solution, extracted withdichloromethane, dried and evaporated solvent to give crude oil. Thismaterial was purified by flash column chromatography on silica gel,eluting with dichloromethane-methanol-ammonia (100:1:1), to give (R)-3d(628 mg, 95%), ¹H NMR (free base, 200 MHz, CDCl₃) δ1.35 (9H, s),1.70-1.87 (4H, m), 2.32-3.16 (6H, m), 3.35-4.46 (6H, m), 4.80-5.68 (6H,m), 7.07-7.45 (8H, m). The compound was used directly into the reactionbelow.

EXAMPLE 7 (R)-4-Asparticacid-1-[(3,4-dichlorophenyl)acetyl]-[(1-pyrrolidinyl)methyl]-piperazinedihydrochloride [(R)-3e 2HCl] ADL-01-0041-2

+The compound (R)-3d was dissolved into 1 ml of HOAc, and HCl (1 ml, 2N)was added, standing 20 min, then hydrogenated at 1 atm., 10% Pd oncarbon at room temperature for 1 h to afford a white salt (R)-3e (430mg, 91.5%): mp 168° C. (d). ¹H NMR (DMSO-d₆) δ1.92-2.16 (4H, m),2.75-5.28 (18H, m), 2.72 (3H, s), 7.31-7.52 (3H, m), 8.45-8.80 (3H, m);MS (FAB) 471 (M+H)⁺; Anal. Calcd for C₂₁H₂₈Cl₂N₄O₄.2HCl: C, 46.34; H,5.18; N, 10.29. Found: C, 45.52; H, 6.02; N. 9.73.

EXAMPLE 8(R)-4-Acetyl-1-[(3,4-dichlorophenyl)acetyl]-2-[(1-pyrrolidinyl)methyl]-piperazinehydrochloride [(R)-3f HCl] ADL-01-0148-5

The compound was prepared as reported in the literature (J. Med. Chem.1993, 36, 2075-2083) from (R)-2. the hydrochloride salt was preparedfrom 1M etherial HCl to afford (R)-3f HCl in 88% yield; mp 153-155° C.;MS (FAB) 398 (M+H)⁺. Anal. Calcd for C₁₉H₂₅Cl₂N₃O₂.HCl.H₂O: C, 52.49; H,6.03; N, 9.66. Found: C, 50.40; H, 6.23; N, 9.28.

EXAMPLE 9(R)-4-Diethoxyphosphonate)-1-[(3,4-dichlorophenyl)acetyl]-2-[(1-pyrrolidinyl)methyl]-piperazinehydrochloride [(R)-3g HCl] ADL-01-0149-3

To a solution of (R)-2 (0.178 g, 0.5 mmol) in 10 mL of CH₂Cl₂ was addedEt₃N (0.101 g, 1.0 mmol) and diethylchlorophosphonate (0.174 g, 1.0mmol) under a nitrogen atmosphere. The reaction mixture was stirred atroom temperature for 13 h and then poured over aqueous 10% K₂CO₃. Theorganic layer was separated, dried over anhydrous Na₂SO₄, and evaporatedto dryness under reduced pressure to give the compound as a yellow oil.The oil was purified on a silica gel column (solvent system:CH₂Cl₂:CH₃OH:28% NH₄OH, 95:5:2) and converted to hydrochloride salt byusual method to give (R)-3g HCl, 0.10 g (38%); mp 168-170° C.; ¹H NMR(free base, 200 MHz, CDCl₃) δ1.20 (6H, t, J=7.0 Hz), 1.64 (4H, m),2.30-2.70 (6H, m), 2.85-3.15 (1H, m), 3.45-3.80 (4H, m), 3.60 (2H, brs),3.98 (4H, m), 4.35 (1H, m), 4.70 (1H, m), 7.00 (1H, m), 7.30 (2H, m); MS(FAB) 492, 494 (M+H)⁺. Anal. Calcd for C₂₁H₃₂Cl₂N₃O₄P.HCl.0.5H₂O: C,46.90; H, 6.37; N, 7.81. Found: C, 46.66; H, 5.90; N, 8.16.

EXAMPLE 10(R)-4-Trifluoroacetyl-1-[(3,4-dichlorophenyl)acetyl]-2-[(1-pyrrolidinyl)methyl]-piperazinehydrochloride [(R)-3h HCl] ADL-01-0150-1

To a solution of (R)-2 (0.356 g, 1.0 mmol) in 10 mL of CH₂Cl₂ was addedEt₃N (0.202 g, 2.0 mmol) and trifluoroacetic anhydride (0.42 g, 2.0mmol) in a nitrogen atmosphere. The reaction mixture was stirred at roomtemperature for 12 h and TLC showed staring material was still present,added another equivalent of trifluoroacetic anhydride and stirring wascontinued for additional 12 h. The reaction was worked up as above andthe hydrochloride salt was prepared as usual to give (R)-3h HCl, 0.25 g(50%); mp 145-147° C.; ¹H NMR (free base, 200 MHz, CDCl₃) δ1.60 (4H, m),2.20-2.75 (6H, m), 3.10 (1H, m), 3.45-3.80 (4H, m), 4.00 (1, J=14.0 Hz,d), ,4.25 (1H, m), 4.45 (1H, J=14.0 Hz, d), 4.70 (1H, m), 7.00 (1H, m),7.28 (2H, m); MS (FAB) 452, 454 (M+H)⁺. Anal. Calcd forC₁₉H₂₂Cl₂F₃N₃O₂.HCl.0.5H₂O: C, 45.85; H, 4.86; N, 8.44. Found: C, 46.26;H, 4.82; N, 8.33.

EXAMPLE 11(R)-4-[(3,4-Dichlorophenyl)acetyl]-3-[(1-pyrrolidinyl)methyl]-1-piperazinecarboxamidehydrochloride [(R)-3i HCl] ADL-01-0151-9

To a solution of (R)-2 (0.356 g, 1.0 mmol) in acetic acid (0.186 g, 3.0mmol) and water was added KOCN (0.244 g, 3.0 mmol) and the reactionmixture was stirred at room temperature for 72 h. An aqueous 10% K₂CO₃was added to the reaction mixture to bring the pH to near 12.0 and theproduct was extracted with CH₂Cl₂, washed with saturated salt solution,dried over anhydrous Na₂SO₄. The removal of solvent at reduced pressuregave the crude product which was purified on a silica gel column(solvent system: CH₂Cl₂:CH₃OH:28% NH₄OH, 95:5:1) to give the desiredproduct as a white solid. The hydrochloride salt was prepared from 1Metheial HCl to give (R)-3i HCl as a white solid, 0.15 g (31%); ¹H NMR(free base, 200 MHz, CDCl₃) δ1.65 (4H, m), 2.10-3.20 (6H, m), 3.40-3.70(4H, m), 3.95 (2H, m), 4.20 (2H, J=14.0 Hz, d,m), 4.70 (1H, m), 5.35(2H, bs), 7.00 (1H, m), 7.25 (2H, m); MS (FAB) 399, 401 (M+H)⁺. Anal.Calcd for C₁₈H₂₄Cl₂N₄O₂.HCl.H₂O.0.125 CH₂Cl₂; C, 46.88; H, 5.91; N,12.06. Found: C, 46.66; H, 5.50; N, 11.97.

EXAMPLE 12(R)-4-[(3,4-Dichlorophenyl)acetyl]-3-[(1-pyrrolidinyl)methyl]-1-piperazinecarboxaldehydehydrochloride [(R)-3j HCl] ADL -01-0156-8

To a solution of (R)-2 (0.356 g, 1.0 mmol) in 10 mL of CH₂Cl₂ was added1.0 mL of methylformate (excess) at 0° C. under a nitrogen atmosphere.The reaction mixture was stirred for 24 h and solvent was removed atreduced pressure to give the crude product. The compound was purified ona silica gel column (solvent system: CH₂Cl₂:CH₃OH:28% NH₄OH, 95:5:1) andconverted to the hydrochloride salt, (R)-3j HCl, 0.10 g (23%); mp 126°C. (d); ¹H NMR (free base, 200 MHz, CDCl₃) δ1.62 (4H, m), 2.10-3.20 (6H,m), 3.35-3.85 (5H, m), 4.25 (3H, m), 4.60 (1H, m), 7.00 (1H, m), 7.26(2H, m), 7.90 (1H, m), MS (FAB) 384, 386 (M+H)⁺.

EXAMPLE 13(R)4-[(3,4-Dichlorophenyl)acetyl]-3-[(1-pyrrolidinyl)methyl]-1-piperazine-sulfonamidehydrochloride [(R)-3k HCl] ADL-01-0164-2

To a solution of (R)-2 (0.356 g, 1.0 mmol) in 5 mL of p-dixane was addedsulfamide⁴ (NH₂SO₂NH₂, 0.96 g, 10 mmol) under a nitrogen atmosphere andthe reaction mixture was heated to reflux for 2 h . The reaction mixturewas evaporated to dryness under reduced pressure and the residue wasredissolved in CH₂Cl₂ and washed with aqueous 10% K₂CO₃, saturated saltsolution, and dried over anhydrous Na₂SO₄. The removal of solventresulted the free base of the product which was purified on a silica gelcolumn (solvent system: CH₂Cl₂:CH₃OH:28% NH₄OH, 98:2:1). Thehydrochloride salt was prepared from 1M etherial HCl to give (R)-3k HCl,0.10 g (21%); mp 183-185° C.; ¹H NMR (free base, 200 MHz, CDCl₃) δ1.68(4H, m), 2.30-3.00 (6H, m), 3.15-4.00 (5H, m), 4.15-4.65 (3H, m), 4.85(1H, m), 7.00 (1H, m), 7.31 (4H, m); MS (FAB) 435 (M+H)⁺. Anal. Calcdfor C₁₇H₂₄Cl₂N₄O₃S.HCl: C, 43.28; H, 5.34; N, 11.87. Found: C, 42.90; H,5.35; N, 11.43.

Ref

(4) Alker, D. et. al. J. Med Chem. 1990, 33, 585.

EXAMPLE 14(R)-4-(4-Methyphenylsulfonyl)-1-[(3,4-dichlorophenyl)acetyl]-2-[(1-pyrrolidinyl)methyl]-piperazinehydrochloride [(R)-3l HCl] ADL-01-0165-9

To a solution of (R)-2 (0.356 g, 1.0 mmol) in 5 mL of CH₂Cl₂ was addedp-toluenesulfonyl chloride (0.38 g, 2 mmol) followed by 0.5 mL ofpyridine under a nitrogen atmosphere. The reaction mixture was stirredat room temperature for 16 h and then poured onto aqueous 10% K₂CO₃. Theorganic layer was separated and dried over anhydrous Na₂SO₄. The removalof solvent gave the product which was purified on a silica gel column(solvent system: CH₂Cl₂:CH₃OH:28% NH₄OH, 98:2:1). The hydrochloride saltwas prepared to give (R)-3l HCl, 0.15 g (27%); mp 240° C. (d); ¹H NMR(free base, 200 MHz, CDCl₃) δ1.65 (4H, m), 1.95-3.00 (6H, m), 2.38 (3H,s), 3.15-3.85 (5H. m), 4.45 (1H, m), 4.75 (1H, m), 6.95 (1H, m), 7.25(4H, m), 7.50 (2H, J=8.0 Hz, d); MS (FAB) 510 (M+H)⁺. Anal. Calcd forC₂₄H₂₉Cl₂N₃O₃S.HCl.0.25H₂O: C, 52.32; H, 5.35; N, 7.63. Found: C, 52.23;H, 7.51.

RACEMIC COMPOUNDS

Racemic compounds were prepared as illustrated by the following steps.

(R,S)-2-[(1-Pyrrolidinyl)methyl]piperazine hydrochloride [(R,S)-4 HCl]

The compound was prepared following the literature procedure¹ andisolated as hydrochloride salt.

(R,S)-4-(R=SO₂CH₃, CO₂CH₃, COCH₃)-2-[(1-Pyrrolidinyl)methyl]piperazinehydrochloride [(R,S)-5,6,7]

These compounds were also prepared according to the procedures describedin the literature¹ and each of the products were purified as free basebefore utilizing below.

EXAMPLE 15(R,S)-4-Methanesulfonyl-1-[(3,4-dichlorophenyl)acetyl]-2-[(1-pyrrolidinyl)methyl]-piperazinehydrochloride [(R,S)-8a HCl] (General Procedure) ADL-01-0135-2

1,1′-Carbonyldiimidazole (0.324 g, 2.0 mmol) was added to a stirredsolution of 3,4-dichlorophenylacetic acid (0.41 g, 2.0 mmol) in 10 mL ofCH₂Cl₂ at room temperature under a nitrogen atmosphere, and theresulting solution was continued stirring for additional 1 h. Theresulting solution was then added to a stirred solution of (R,S)-5(0.247 g, 1.0 mmol) in 10 mL of CH₂Cl₂ at 0° C. and the reaction mixturewas stirred for further 20 h. The reaction mixture was diluted withCH₂Cl₂ and washed with aqueous 2M Na₂CO₃. The organic layer was driedand evaporated to dryness and the product was purified on a silica gelcolumn (solvent system: CH₂Cl₂:CH₃OH:28% NH4OH, 98:2:1). Thehydrochloride salt was prepared by redissolving the compound in CH₂Cl₂and treating the solution with 1M etherial HCl to give (R,S)-8a HCl as awhite solid, 0.20 g (32%); NMR (see R-3a); MS (FAB) 434 (M+H)⁺; Anal.Calcd for C₁₈H₂₅Cl₂N₃O₃S.HCl.0.5H₂O: C, 45.13; H, 5.51; N, 8.77. Found:C, 45.46; H, 5.36; N, 8.71.

The following compounds were similarly prepared from (R,S)-5, 6,and 7:

EXAMPLE 16(R,S)-4-Methanesulfonyl-1-[(4-methylsulfonylphenyl)acetyl]-2-[(1-pyrrolidinyl)-methyl]piperazinehydrochloride [(R,S)-8b HCl] ADL-01-0117-0

The compound was prepared from 4-methylsulfonylphenylacetic acid and thehydrochloride salt was recrystallized from CH₃OH to give (R,S)-8b HCl in60% yield; mp 185-188° C.; ¹H NMR (free base, 200 MHz, CDCl₃) δ1.65 (4H,m), 2.30-2.70 (6H, m), 2.80 (3H, s), 2.85-3.10 (3H, m), 3.00 (2H, m),3.25 (1H, m), 3.50-3.95 (4H, m), 4.50 (1H, m), 4.80 (1H, m)), 7.40 (2H,J=7.5 Hz, d), 7.80 (2H, J=7.5 Hz, d); MS (FAB) 444 (M+H)⁺; Anal. Calcdfor C₁₉H₂₉N₃O₅S₂. HCl: C, 47.54; H, 6.30; N, 8.75. Found: C, 46.03; H,6.24; N, 8.80.

EXAMPLE 17(R,S)-4-Methanesulfonyl-1-[(2-nitrophenyl)acetyl]-2-[(1-pyrrolidinyl)-methyl]piperazinehydrochloride [(R,S)-8c HCl] ADL-01-0119-6

The compound was prepared from 2-nitrophenylacetic acid in 65% yield ashydrochloride salt; mp 253-255° C.; ¹H NMR (free base, 200 MHz, CDCl₃)δ1.70 (4H, m), 2.40-3.10 (6H, m), 2.75 (3H, s), 3.45 (1H, m), 3.70-4.00(4H, m), 4.05-4.30 (2H, m), 4.50 (1H, m), 4.72 (1H, m), 7.45 (3H, m),8.05 (1H, J=8.0 Hz, d); MS (FAB) 411 (M+H)⁺; Anal. Calcd forC₁₈H₂₆N₄O₅S.HCl: C, 48.37; H, 6.09; N, 12.54. Found: C, 48.36; H, 5.66;N, 12.29.

EXAMPLE 18(R,S)-4-Methanesulfonyl-1-[(4-trifluoromethylphenyl)acetyl]-2-[(1-methyl]piperazinehydrochloride [(R,S)-8d HCl] ADL-01-0120-4

The compound was prepared as a hydrochloride salt from4-trifluorometylphenylacetic acid in 82% yield; 182-185° C.; ¹H NMR(free base, 200 MHz, CDCl₃) δ1.65 (4H, m), 2.35-3.05 (6H, m), 2.71 (3H,s), 3.25 (1H, m), 3.50-3.95 (5H, m), 4.55 (1H, m), 4.85 (1H, m), 7.30(2H, m), 7.50 (2H, J=7.8 Hz, d); MS (FAB) 434 (M+H)⁺; Anal. Calcd forC₁₉H₂₆F₃N₃O₃S.HCl.0.5H₂O: C, 47.65; H, 5.89; N, 8.77. Found: C, 48.36;H, 5.80; N, 8.51.

EXAMPLE 19(R,S)-4-Methanesulfonyl-1-[(3-indolylacetyl]-2-[(1-pyrrolidinyl)-methyl]piperazinehydrochloride [(R,S)-8e HCl] ADL-01-0134-5

The compound was prepared from 3-indoleacetic acid and isolated as freebase in 40% yield and converted to hydrochloride salt; mp 219-221° C.;¹H NMR (free base, 200 MHz , CDCl₃) δ1.65 (4H, m), 2.10-3.00 (6H, m),2.55 (3H, S), 3.10-3.45 (2H, m), 3.45-3.90 (4H, m), 4.05 (1H, m), 4.55(1H, m), 4.90(1H, m), 7.05 (3H, m), 7.25 (1H, m), 7.50 (1H, m), 8.95(1h, bs); MS (FAB) 405 (M+H)⁺; Anal. Calcd for C₂₀H₂₈N₄O₃S.HCl.0.5H₂O:C, 58.09; H, 7.07; N, 13.55. Found: C, 58.37; H, 6.68; N, 13.30.

EXAMPLE 20 (R,S)-Methyl4-[(4-methylsulfonylphenyl)acetyl]-3-[(1-pyrrolidinyl)-methyl]-1-piperazinecarboxylatehydrochloride [(R,S)-9a HCl] ADL-01-0092-5

The compound was prepared from 4-methylsulfonylphenylacetic acid and thehydrochloride was prepared from 1M etherial HCl to give (R,S)-9a HCl in46% yield; mp 225° C.; ¹H NMR (free base, 200 MHz, CDCl₃) δ1.60 (4H, m),2.15-2.95 (6H, m), 2,98 (3H, s), 3.15 (2H, m), 3.35 (3H, m), 3.60 (3H,s), 3.95 (2H, m), 4.30 (1H, m), 4.72 (1H, m), 7.45 (2H, m), 7.75 (2H,J=7.5 Hz, d); MS (FAB) 424 (M+H)⁺; Anal. Calcd forC₂₀H₂₉N₃O₅S.HCl.0.25H₂O: C, 51.72; H, 6.62; N, 9.05. Found: C, 51.93; H,6.47; N, 8.44.

EXAMPLE 21 (R.S)-Methyl4-[(4-trifluoromethylphenyl)acetyl]-3-[(1-pyrrolidinyl)-methyl]-1-piperazinecarboxylatehydrochloride [(R,S)-9b HCl] ADL-01-0094-1

The compound was prepared as a hydrochloride salt from4-trifluorometylphenylacetic acid to give (R,S)-9b HCl in 48%; mp 210°C.; ¹H NMR (200 MHz, CDCl₃) δ1.50 (4H, m), 1.95-2.30 (6H, m), 2.35-3.50(4H, m), 3.65 (3H, S), 3.70-4.50 (5H, m), 7.45 (4H, m); MS (FAB) 414(M+H )⁺; Anal. Calcd for C₂₀H₂₆F₃N₃O₃.HCl.0.25H₂O: C, 52.86; H, 6.10; N,9.25. Found: C, 53.03; H, 5.94; N, 8.94.

Another minor product (R,S)-11 (ADL-01-0093-3) was isolated as ahydrochloride salt from this reaction in 10% yield; mp 190° C.; MS (FAB)446 (M+H)⁺.

EXAMPLE 22 (R,S)-Methyl4-[(3-indoyl)acetyl]-3-[(1-pyrrolidinyl)-methyl]-1-piperazine-carboxylatehydrochloride [(R,S)-9c HCl] ADL-01-0095-8

The compound was prepared from 3-indoleacetic acid and the hydrochloridesalt was prepared to give (R,S)-9c HCl in 75% yield; mp 143° C.; ¹H NMR(200 MHz, CDCl₃) δ1.55 (4H, m), 1.90-2.52 (6H, m), 2.70-3.75 (9H, m),3.35 (3H, S), 6.60 (2H, m), 6.85 (2H, m), 7.20 (1H, s), 7.65 (1H, brs);MS (FAB) 385 (M+H)⁺.

EXAMPLE 23 (R,S)-Methyl4-[(2-nitrophenyl)acetyl]-3-[(1-pyrrolidinyl)-methyl]-1-piperazine-carboxylatehydrochloride [(R,S)-9d HCl] ADL-01-0096-6

The compound was prepared from 2-nitrophenyacetic acid and hydrochloridewas prepared from 1M etherial HCl to give (R,S)-9d HCl in 42% yield; mp228° C.; ¹H NMR (free base, 200 MHz, CDCl₃) δ1.60 (4H, brs), 1.80-2.30(4H, m), 2.70 (2H, m), 3.05 (2H, m), 3.60 (3H, s), 3.55-4.10 (4H, m),4.35 (2H, J=14.0 Hz, dd), 5.10 (1H, m), 7.50 (3H, m), 8.05 (1H, J=7.5Hz, d); MS (FAB) 391 (M+H)⁺; Anal. Calcd for C₁₉H₂₆N₄O₅.HCl: C, 53.46;H, 6.37; N, 13.12. Found: C, 54.29; H, 6.38; N, 12.58.

EXAMPLE 24 (R,S)-Methyl4-[(2-methoxyphenyl)acetyl]-3-[(1-pyrrolidinyl)-methyl]-1-piperazine-carboxylatehydrochloride [(R,S)-9e HCl] ADL-01-0097-4

The compound was prepared as above from 2-methoxyphenylacetic acid togive (R,S)-9e HCl in 12% yield; mp 120° C.; ¹H NMR (free base, 200 MHz,CDCl₃) δ1.65 (4H, m), 2.25-2.95 (6H, m), 3.10 (1H, m), 3.30-4.10 (5H,m), 3.60 (3H, s), 3.70 (3H, s), 4.40 (1H, m), 4.70 (1H, m), 6.84 (2H,m), 7.15 (3H, m); MS (FAB) 376 (M+H)⁺; Anal. Calcd forC₂₀H₂₉N₃O₄.HCl.H₂O: C, :55.87; H, 7.50; N, 9.77. Found: C, 55.78; H,6.97; N, 9.42.

EXAMPLE 25 (R,S)-Methyl4-[(2-aminophenyl)acetyl]-3-[(1-pyrrolidinyl)-methyl]-1-piperazine-carboxylatedihydrochloride [(R,S)-9f 2HCl] ADL-01-0098-2

The compound was prepared by the hydrogenation of (R,S)-9e HCl on 10%Pd/C following the procedure described in the literature1. The compound,(R,S)-9f 2HCl, was isolated as dihydrochloride in 84% yield; mp 195° C.(d); ¹H NMR (200 MHz, DMSO-d₆) δ2.00 (4H, m), 3.05-4.45 (16H, m), 3.75(3H, s), 5.00 (1H, m), 7.45 (4H, brs); MS (FAB) 361 (M+H)⁺; Anal. Calcdfor C₁₉H₂₈N₄O₃.2HCl.H₂O: C, 50.56; H, 7.15; N, 12.41. Found: C, 50.36;H, 7.26; N, 12.05.

EXAMPLE 26(R,S)-4-Acetyl-1-[(4-methylsulfonylphenyl)acetyl]-3-[(1-pyrrolidinyl)-methyl-piperazinehydrochloride [(R,S)-10a HCl] ADL-01-0144-4

The compound was prepared as above from 4-methylsulfonylphenylaceticacid and the hydrochloride salt was prepared in usual fashion to give(R,S)-10a HCl in 45% yield; mp 145-147° C.; ¹H NMR (200 MHz, DMSO-d₆)δ1.90 (4H, m), 2.17 (3H, s), 2.65-3.80 (6H, m). 3.32 (3H, s), 3.85-4.45(8H, m), 5.05 (1H, m), 7.65 (2H, J=8.0 Hz, d), 7.95 (2H, J=8.0 Hz, d);MS (FAB) 408 (M+H)⁺.

EXAMPLE 27(R,S)-4-Acetyl-1-(4-trifluoromethylphenyl)acetyl]-3-[(1-pyrrolidinyl)-methyl]piperazinecarboxylatehydrochloride [(R,S)-10b HCl] ADL-01-0145-1

The compound was prepared from 4-trifluorometylphenylacetic acid andisolated as hydrochloride salt, (R,S)-10b HCl, in 30% yield; mp 110° C.;¹H NMR (200 M DMSO-d6) δ2.00 (4H, m), 2.15 (3H, s), 2.70-3.25 (6H, m),3.50-4.45 (8H, m), 5.05 (1H, m), 7.70 (4H, m); MS (FAB) 398 (M+H)⁺.

EXAMPLE 28(R,S)-4-Acetyl-1-[(2-triflouromethylphenyl)acetyl]-3-[(1-pyrrolidinyl)-methyl]piperazinecarboxylatehydrochloride [(R,S)-10c HCl] ADL-01-0157-6

The compound was prepared from 2-trifluorometylphenylacetic acid and thehydrochloride salt was made from 1M eterial HCl to give (R,S)-10c HCl in57%; 220° C. (d); ¹H NMR (free base, 200 MHz, CDCl₃) δ1.65 (4H, m), 2.05(3H, s), 2.25-3.25 (6H, m), 3.40-4.10 (6H, m), 4.50 (2H, m), 4.70 (1H,m), 7.30 (2H, m), 7.60 (2H, m); MS (FAB) 398 (M+H)⁺.

EXAMPLE 29(R,S)-4-Acetyl-1-[(3-nitrophenyl)acetyl]-3-[(1-pyrrolidinyl)-methyl]piperazine-carboxylatehydrochloride [(R,S)-10d HCl] ADL-01-0158-4

The compound was prepared from 3-nitrophenylacetic acid and thehydrochloride salt, (R,S)-10d HCl was isolated as a white solid in 69%yield; mp 143-145° C.; ¹H NMR (free base, 200 MHz, CDCl₃) δ1.63 (4H,brs), 2.05 (3H, s), 2.20-2.80 (6H, m), 2.90-3.25 (2H, m), 3.50-3.90 (3H,m), 4.00 (1H, J=14.0 Hz, d), 4.45 (2H, m), 4.65 (1H, m), 7.45 (2H, m),8.00 (2H, m), MS (FAB) 375 (M+H)⁺; Anal. Calcd for C₁₉H₂₆N₄O₄.HCl.H₂O:C, 53.21; H, 6.81; N, 13.06. Found: C, 53.51; H, 6.13; N, 12.91.

EXAMPLE 30(R,S)-4Acetyl-1-[(2-nitrophenyl)acetyl]-3-[(1-pyrrolidinyl)-methyl]piperazine-carboxylatehydrochloride [(R,S)-10e HCl] ADL-01-0163-4

The compound was prepared as above from 2-nitrophenylacetic acid to give(R,S)-10e HCl as white solid in 50% yield; mp 180° C. (d); ¹H NMR (freebase, 200 MHz, CDCl₃) δ1.63 (4H, m), 2.04 (3H, s), 2.20-2.85 (6H, m),2.98-3.35 (3H, m), 3.60-4.25 (4H, m), 4.60 (2H, m), 7.35 (3H, m), 8.00(1H, J=7.0 Hz, d); MS (FAB) 375 (M+H)⁺; Anal. Calcd forC₁₉H₂₆N₄O₄.HCl.0.5H₂O: C., 55.54; H, 6.62; N, 13.64. Found: C, 54.38; H,6.35; N, 13.58.

EXAMPLE 31(R,S)-4-Acetyl-1-[(4-nitrophenyl)acetyl]-3-[(1-pyrrolidinyl)-methyl]piperazine-carboxylatehydrochloride [(R,S)-10f HCl] ADL-01-0159-2

The compound was prepared from 2-nitrophenylacetic acid as before togive (R,S)-10f HCl in 52% yield; 146-148° C.; ¹H NMR (free base, 200MHz, CDCl₃) δ1.68 (4H, m), 2.07 (3H, s), 2.20-2.75 (6H, m), 3.40-3.90(3H, m), 4.05 (1H, J=13.5 Hz, d), 4.50 (2H, m), 7.35 (2H, J=8.0 Hz, d),8.10 (2H, J=8.0 Hz, d); MS (FAB) 375 (M+H)⁺; Anal. Calcd forC₁₉H₂₆N₄O₄HCl.0.5H₂O.0.125CH₂Cl₂: C, 53.36; 6.61; 13.01. Found: C,53.16; H, 6.27; N, 13.36.

EXAMPLE 32(R,S)-4-(Phenylmethyl)-1-[(4,5,-dichloro-2-nitrophenyl)acetyl]-2-[(1-pyrrolidinyl)methyl]piperazinedihydrochloride [(R,S)-12 2HCl] ADL-01-0166-7

The compound was prepared from4-phenylmethyl-2[(1-pyrrolidinyl)methyl]piperazine (Ref. 1) and4,5-dichloro-2-nitrophenylacetic acid following the method describedabove to give (R,S)-12 2HCl in 63% yield; mp 235° C. (d); ¹H NMR (freebase, 200 MHz, CDCl₃) δ1.66 (4H, m), 2.05-3.00 (8H, m), 3.45 (4H, m),4.00 (5H, m), 4.60 (1H, m), 7.35 (6H, m), 8.15 (1H, s); MS (FAB) 493(M+H)⁺; Anal. Calcd for C₂₄H₂₉Cl₂N₄O₃.2HCl: C, 50.99; 5.53; 9.91. Found:C, 50.55; H, 5.16; N, 9.44.

The preparation of compounds of formula IA (compounds 1a through 1qq)follow according to Schemes A, 1B, C, D,E and F.

EXAMPLE 1aMethyl-4-[-2-glycyl-4-(trifluoromethylphenyl)acetyl]-3-(R,S)-[(1-pyrrolidinyl)-methyl]-1-piperazinecarboxylateMethyl-4-[(2-nitro-4-trifluoromethylphenyl)acetyl]-3-(R,S)-[(1-pyrrolidinyl)-methyl]-1-piperazinecarboxylate¹(ProcedureA) (a)

To a solution of 2-nitro-4-trifluorophenylacetic acid (2.8 g, 11.2 mmol)in 30 mL of dry CH₂Cl₂ under a nitrogen atmosphere was added HOBt (1.3g., 9.6 mmol). The reaction mixture is stirred at 0° C. and added solidEDCI (2.25 g, 11.75 mmol). Then, stirred for 30 minutes at 0° C. Asolution ofmethyl-3-(R,S)-[(1-pyrrolidinyl)methyl]-1-piperazinecarboxylate¹ (2.0 g,8.78 mmol) in 5 mL of dry CH₂Cl₂ was added followed by DIEA (1.68 mL,9.64 mmol). The reaction mixture was stirred for 24 h while warming toroom temperature. The reaction mixture was then poured into water (50mL) and stirred for 30 minutes. After dilution with CH₂Cl₂, the organiclayer was separated, washed with saturated NaHCO₃, salt solution, andwater. Then, dried over Mg₂SO₄. The compound was purified by flashcolumn chromatography on silica gel, eluting with CH₂Cl₂:CH₃OH:(98:2) togive the desired product as a free base(3.15 g, 78% yield). Then,proceed on to the next step. ¹H NMR (free base 200 MHz CDCl₃) δ1.76 (4H,m), 2.65 (4H, m),3.02 (2H, m), 3.74 (s, 3H),4.21 (4H, m), 7.56 (dd,J=2.4,8.0 Hz, 1H), 7.85 (d, J=8.0 Hz, 1H), 8.4 (d, J=2.4 Hz, 1H);MS(FAB) m/z 459.

Methyl-4-[(2-amino-4-trifluoromethylphenyl)acetyl]-3-(R,S)-[(1pyrrolidinyl)-methyl]-1-piperazinecarboxylatehydrochloride (b)

Compound a (1.18 gm, 2.57 mmol) was dissolved in ethanol (50 mL) andheated to 55° C. Hydrazine hydrate(0.9 mL, 28.12 mmol) and 1 scoop ofRaney Nickel was added to the reaction flask. Stir vigorously. Continueto add the Raney Nickel until all of the hydrazine is consumed (when thebubbling has stopped). Cool to 30° C. and filter through celite and washwith hot methanol. (Do not allow the Raney nickel to become dry!).Evaporate the solvent and generate an HCl salt(1.0 gm; 90.6%); m.p.160-165° C. ¹H NMR (free base 200 MHz, CDCl₃) δ1.76 (4H, m), 2.5-3.1(7H, m), 3.74 (3H, s), 4.15 (2H, m), 4.55 (2H, m), 6.90 (1H, J=2.4 Hz,d), 6.95 (1H, J=2.4, 8.0 Hz, dd), 7.15 (1H, J=8.0 Hz, d). MS (FAB) m/z429. Anal. Calc. For C₂₀H₂₇N₄F₃O₃.HCl.H₂O: C, 49.69; H, 6.21; N, 11.60.Found: C, 49.57; H, 6.04; N, 11.32.

To a solution of bromoacetic acid(0.356 g, 2.56 mmoL) and DIEA(1.0 mL,5.74 mmoL) in CH₃CN(15 mL) was added compound b and heated to 55° C. for16 hr. Then, heated to 75° C. for 4 hr. The reaction was complete.Evaporate the solvent and re-dissolve in ethanol(25.0 mL). Add 0.1 MNa₂CO₃ (20 mL) and filter and wash with boiling ethanol (15 mL).Evaporate the filtrate and dissolve in isopropanol (10 mL). Add diethylether (5.0 mL) until precipitate forms. Filtered. A white solid isobtained(m.p. 165-170° C.; 0.3 g, 24.8% yield). ¹H NMR (free base 200MHz, CDCl₃) d 2.19(4H, m), 2.95 (4H, m), 3.2-3.7 (4H,m), 3.74 (3H, s),3.8-4.2 (4H, m), 4.7 (1H, m), 5.2 (1H, m), 6.86 (1H, J=2.4 Hz, d), 7.0(2H, J=8.0 Hz, d). MS (FAB) m/z 487. Anal. Calc. ForC₂₂H₂₉N₄F₃O₅.0.5C₂H₆O.0.5H₂O: C, 53.28; H, 6.37; N, 10.81. Found: C,53.50; H, 6.25; N, 10.51.

EXAMPLE 1bMethyl-4-[(2-[N,N-bis-methylsulfonamido]-4-trifluoromethyphenyl)acetyl]-3-(R,S)-[(1-pyrrolidinyl)-methyl]-1-piperazinecarboxylatedihydrochloride

To a solution of compound b (0.4 g, 0.933 mmoL) and triethylamine(0.26mL, 1.86 mmoL) in CH₂Cl₂(10.0 mL) at 0° C. was added methanesulfonylchloride(0.144 mL, 1.86 mmoL). The reaction was stirred for 16 hr. Thereaction was diluted with CH₂Cl₂(40.0 mL), washed with saturated NaHCO₃solution and water. Then, dried over Mg₂SO₄. Then, isolated on a silicagel column (solvent system: CH₂Cl₂:CH₃OH:28% NH₄OH (98:2:2) to give thedesired product as a free base (0.4 g, 73%). Evaporate the solvent andgenerate an HCl salt(0.14 gm; m.p. 155-160° C.). ¹H NMR (free base 200MHz, CDCl₃) δ1.76 (4H, m), 2.75-3.31 (11H, m),3.47 (3H, s), 3.50 (3H,s), 3.72 (3H, s), 3.8-4.3(5H, m), 4.55 (1H, m), 4.95 (1H, m),7.5-7.9(3H, Ar). MS (FAB) m/z 585. Anal. Calc. For C₂₂H₃₁N₄F₃O₇S₂.2HCl:C, 42.54; H, 5.19; N, 9.02. Found: C, 42.58; H, 5.23; N, 8.91.

EXAMPLE 1cMethyl-4-[(2-[N-methylsulfonamido]phenyl)acetyl]-3-(R,S)-[(1-pyrrolidinyl)methyl]-1-piperazinecarboxylatehydrochlorideMethyl-4-[2-nitro-phenyl)acetyl]-3-(R,S)-[(1-pyrrolidinyl)methyl]-1-piperazinecarboxylate(c)

The compound was prepared from 2-nitro-phenylacetic acid followingProcedure A and isolated on a silica gel column (solvent system:CH₂Cl₂:CH₃OH:28% NH₄OH (99:1:2) to give the desired product as a freebase (3.15 g, 78%). Then, proceed on to the next step. ¹H NMR (free base300 MHz, CDCl₃) d 1.75 (4H, m), 2.53 (4H, m),3.02 (2H, m), 3.74 (s,3H),4.21 (4H, m),7.4 (1, ArH,m) 7.56 (1H, J=1.2 Hz, d), 7.61 (1H, J=1.2,7.4 Hz, dd), 8.11 (1H, J=8.0 Hz, d).

Methyl-4-[(2-amino-phenyl)acetyl]-3-(R,S)-[(1-pyrrolidinyl)methyl]-1-piperazinecarboxylate(d)

Then, compound c was dissolved in ethanol(200 mL) and Pd/C (Degussa;10%; 3.0 g) were added into a Parr bottle (500 mL). Then, the bottle wasattached to a Parr Shaker Hydrogenator at 50 psi for 6 hr. The reactionwas complete. This was filtered through celite. Evaporate the solventand proceed on to the final step.

Then, to a solution of the above compound d (0.15 g, 0.33 mmoL) andtriethylamine(0.10 mL, 0.66 mmoL) in CH₂Cl₂(10.0 mL) at 0° C. was addedmethanesulfonyl chloride(0.026 mL, 0.33 mmoL). The reaction was stirredfor 16 hr. The reaction was diluted with CH₂Cl₂(20.0 mL), washed withsaturated NaHCO₃ solution and water. Then, dried over Mg₂SO₄. Then,isolated on a silica gel column (solvent system: CH₂Cl₂:CH₃OH:28% NH₄OH(98:2:2) to give the desired product as a free base (0.1 g, 68%).Evaporate the solvent and generate an HCl salt(0.06 gm; m.p. 130-135°C.). ¹H NMR (free base 200 MHz, CDCl₃) δ1.75 (4H, m),2.2 (1H, m),2.5-3.1 (6H, m),3.01 (3H, s),3.50 (2H, m), 3.73 (3H, s), 3.8-4.5(5H, m),5.02 (1H, m), 6.88-7.55(3H, Ar). MS (FAB) m/z 439. Anal. Calc. ForC₂₀H₃₀N₄O₅S₂.HCl: C, 50.57; H, 6.58; N, 11.79. Found: C, 50.55; H, 6.64;N, 11.36.

EXAMPLE 1dMethyl-4-[(2-[N,N-bis-methylsulfonamido]phenyl)acetyl]-3-(R,S)-[(1-pyrrolidinyl)methyl]-1-piperazinecarboxylatehydrochloride

To a solution of the compound d (0.70 g, 1.94 mmoL) andtriethylamine(0.44 mL, 3.19 mmoL) in CH₂Cl₂(10.0 mL) at 0° C. was addedmethanesulfonyl chloride(0.247 mL, 3.19 mmoL). The reaction was stirredfor 16 hr. The reaction was diluted with CH₂Cl₂(20.0 mL), washed withsaturated NaHCO₃ solution and water. Then, dried over Mg₂SO₄. Then,isolated on a silica gel column (solvent system: CH₂Cl₂:CH₃OH:28% NH₄OH(98:2:2) to give the desired product as a free base (0.7 g, 70%).Evaporate the solvent and generate an HCl salt(0.75 g; m.p. 145-150°C.). ¹H NMR (free base 200 MHz, CDCl₃) δ1.76 (4H, m),2.2 (1H, m),2.5-3.1 (6H, m),3.44 (3H, s),3.49 (3H, s), 3.71 (3H, s), 3.8-4.5(5H, m),4.50 (1H, m),4.89 (1H, m), 7.23-7.75(3H, Ar). MS (FAB) m/z 517. Anal.Calc. For C₂₁H₃₂N₄O₇S₂.HCl: C, 46.05; H, 6.22; N, 10.09. Found: C,45.60; H, 6.01; N, 10.13.

EXAMPLE 1eMethyl-4-[(2-[N-methylamino)sulfamyl]phenyl)acetyl]-3-(R,S)-[(1-pyrrolidinyl)methyl]-1-piperazinecarboxylatehydrochloride

The compound was prepared from (N-methylamino)sulfamyl phenyl aceticacid (a mixture of the ortho and para isomer) following Procedure A andisolated on a silica gel column [solvent system: CH₂Cl₂:CH₃OH:28% NH₄OH(99:2:1): R_(f)=0.56] to give the desired product as a free base (0.70g, 70%). Then, generate the HCl salt(m.p. 155-160° C.; 0.31 g). ¹H NMR(free base 200 MHz, CDCl₃) δ1.75 (m,4H), 2.53 (m,4H), 2.66 (d, J=5.2 Hz,3H),2.82 (m, 3H), 3.25 (m, 1H), 3.72 (s, 3H),3.84 (m, 2H), 4.15 (m, 2H),4.50 (m, 1H),4.85 (m, 1H),7.45 (dd, J=4.0, 8.2 Hz, 2H) 7.79 (d, J=8.0 H,1H), 7.83 (d,J=8.2 Hz, 1H); MS(FAB) m/z 439. Anal. Calc. ForC₂₀H₃₀N₄O₅S.HCl: C, 50.13; H, 6.61; N, 11.36. Found: C, 50.57; H, 6.58;N, 11.79.

EXAMPLE 1fMethyl-4-[-4-[N-methylamino)sulfamyl]phenyl)acetyl]-3-(R,S)-[(1-pyrrolidinyl)methyl]-1-piperazinecarboxylatehydrochloride

The compound was isolated from the above reaction on a silica gelcolumn[solvent system: CH₂Cl₂:CH₃OH:28% NH₄OH (99:1:2): R_(f)=0.62] togive the desired product as free base. Then, generate the HCl salt(m.p.135-140° C.; 6.0 mg). ¹H NMR (free base 200 MHz, CDCl₃) δ1.74 (m,4H),2.53 (m, 4H), 2.66 (d, J=5.2 Hz, 3H), 2.82 (m, 3H), 3.25 (m, 1H), 3.71(s, 3H),3.84 (m, 2H), 4.15 (m, 2H), 4.50 (m, 1H),4.85 (m, 1H),7.48 (m,2H, ArH) 7.73 (m, 2H, ArH); MS(FAB) m/z 439. Anal. Calc. ForC₂₀H₃₀N₄O₅S.HCl: C, 50.13; H, 6.61; N, 11.36. Found: C, 50.57; H, 6.58;N, 11.7.

EXAMPLE 1g4-Trifluoroacetyl-1-[(trans-3-furanacyrlate]-2-(R,S)-(1-pyrrolidinyl)methyl]piperazinehydrochloride 4-Trifluoroacetyl-2-(R,S)-(1-pyrrolidinyl)methylpiperazine(e)

To a solution of (R,S)2-(1-pyrrolidinyl)methyl]piperazine hydrochloride(1.0 g, 3.58 mmol) and Et₃N (0.5 mL, 3.58 mmol) in 10 mL of CH₂Cl₂ wasadded trifluoroacetic anhydride (0.5 mL, 3.58 mmol) at 0° C. Thereaction mixture is stirred at 0° C. for 5 h. The reaction mixture wasevaporated under reduced pressure (due to the water solubility of thiscompound there was no aqueous work-up) and isolated on a silica gelcolumn (solvent system: CH₂Cl₂:CH₃OH:28% NH₄OH (98:2:2) to give thedesired product as a free base (0.18 g, 20%); ¹H NMR (free base 200 MHz,CDCl₃) d 1.76 (m,4H), 2.25-3.15 (m, 10H), 3.26 (t, 2H), 3.88 (m, 1H),4.39 (t, 1H).

To a solution of trans-3-furanacyrlic acid (0.10 g, 0.74 mmol) in 5 mLof dry CH₂Cl₂ under a nitrogen atmosphere was added HOBt (0.10 g., 0.74mmol). The reaction mixture is stirred at 0° C. and added solid EDCI(0.143 g, 0.75 mmol). Then, stirred for 30 minutes at 0° C. A solutionof compound e (0.18 g, 0.67 mmol) in 5 mL of dry CH₂Cl₂ was addedfollowed by DIEA (0.177 mL, 1.01 mmol). The reaction mixture was stirredfor 24 h while warming to room temperature. The reaction mixture wasthen poured into water (50 mL) and stirred for 30 minutes. Afterdilution with CH₂Cl₂, the organic layer was separated, washed withsaturated NaHCO₃, salt solution, and water. Then, dried over Mg₂SO₄. Thecompound was purified by flash column chromatography on silica gel,eluting with CH₂Cl₂:CH₃OH:28% NH₄OH(99:1:2) to give the desired productas a free base(m.p. 144-145° C.; 0.25 g, 95% yield). The hydrochloridesalt was prepared from 1M etheral HCl.(0.1 g) ¹H NMR (free base 200 MHz,CDCl₃) δ1.74 (m, 4H), 2.57 (m, 5), 3.11 (m, 2H), 3.31 (m, 2H), 4.05 (m,1H), 4.25 (m, 1H), 4.50 (m, 1H), 4.65 (m, 1H), 6.58 (d, J=3.3, 7.8 Hz,2H), 7.44 (m, 1H), 7.64 (d, J=3.3 Hz, 2H); MS (FAB) m/z 386; Anal.Calcd. For C₁₈H₂₂N₃F₃O₃.HCl: C, 51.25; H, 5.50; N, 9.96. Found: C,51.44; H, 5,57; N, 9.86.

EXAMPLE 1h4-Trifluoroacetyl-1-[(-4-trifluoromethylphenyl)acetyl]-2-(R,S)-(1-pyrrolidinyl)methyl]piperazinehydrochloride

To a solution of 4-triflouromethyl-phenyl acetic acid (0.08 g, 0.39mmol) in CH₂Cl₂ (5.0 mL) was added 1,1′ carbonyldiimidazole (0.06 g,0.39 mmol) under a nitrogen atmosphere and stirred for 1 h. Cool to 0°C. and compound e (0.1 g, 0.39 mmol) in CH₂Cl₂ (5.0 mL) was added. Then,stirred for 16 h and the reaction mixture was then poured into asolution of ice-cold saturated NaHCO₃ and stirred for 30 minutes. Afterdilution with CH₂Cl₂, the organic layer was separated, washed withsaturated salt solution, and dried over Mg₂SO₄. The compound waspurified by flash column chromatography on silica gel, eluting withCH₂Cl₂:CH₃OH:28% NH₄OH(99:1:2) to give the desired product as a freebase(m.p. 140-145° C.; 0.08 g, 47% yield). The hydrochloride salt wasprepared from 1M etheral HCl.(0.05 g) ¹H NMR (free base 200 MHz, CDCl₃)δ1.75 (m, 4H), 2.55 (m, 5H), 2.69-3.2 (m, 4H), 3.8 (m, 1H), 3.83 (m,2H), 4.50 (m, 1H), 4.65 (m, 1H), 7.38 (d, J=7.7 Hz, 2H), 7.64 (d, J=7.8Hz, 2H); MS (FAB) m/z 452; Anal. Calcd. For C₂₀H₂₃N₃F₃O₂.HCl0.3Et₂O: C,49.96; H, 5.30; N, 8.24. Found: C, 49.62; H, 5.16; N, 7.84.

EXAMPLE 1iMethyl-4-[(3,4-dichlorophenyl)acetyl]-3-(R,S)-[(4′-methylpiperazinecarboxylate)methyl]-1-piperazinecarboxlyatehydrochloride

The compound was prepared by coupling of 3,4-dichlorophenylacetic acidwith methyl-3(R,S)-[(4′-methylpiperazinecarboxylate)methyl]-1-piperazinecarboxylate;mp: (HCl salt)160-165° C.; ¹H NMR (free base, 200 MHz, CDCl₃) δ1.5-1.8(2H, m), 2.2-3.2 (8H, m), 3.3-3.5 (5H, m), 3.6 (3H, s), 3.7 (3H, s),3.9-4.5 (3H, m), 4.7-4.8 (1H, m), 7.1 (1H, m), 7.4 (2H, m); MS (FAB) 487(M+H)⁺; Anal. Calcd. for C₂₁H₂₈Cl₂N₄O₅.HCl.H₂O: C, 46.55; H, 5.77; N,10.34. Found: C, 46.02; H, 5.93; N, 10.91.

EXAMPLE 1jMethyl-4-[(4-a,a,a-trifluoromethylphenyl)acetyl]-3-(R,S)-[3-(S)-(4′-α,α,α-trifluoromethylphenylacetate)-1-(pyrrolidinyl)methyl]-1-piperazinecarboxylatehydrochloride (1j)

The compound was prepared by coupling of4-α,α,α-trifluoromethylphenyl-acetic acid withmethyl-3-(R,S)-[3-(S)-hydroxy-1-(pyrrolidinyl)methyl]-1-piperazinecarboxylate; mp: (HCl salt)98-100° C.; ¹H NMR (free base, 200 MHz,CDCl₃) δ1.6-3.1 (11H, m), 3.4-5.4 (12H, m),7.1-7.7 (8H, m); MS (FAB) 616(M+H)⁺; Anal. Calcd for C₂₉H₃₁F₆N₃O₅.HCl.H₂O.0.25NH₄Cl: C, 50.97; H,5.16; N, 6.66. Found: C, 50.45; H, 5.07; N, 6.67.

EXAMPLE 1kMethyl-4-[(3,4-dichlorophenyl)acetyl]-3-(R,S)-[(2-(S)-pyrrolidinemethyl-3′,4′-dichlorophenylacetate)methyl]-1-piperazinecarboxylate hydrochloride

The compound was prepared by coupling of 3,4-dichlorophenylacetic acidwithmethyl-3-(R,S)-[(2-(S)-pyrrolidinemethanol)methyl]-1-piperazinecarboxylate;mp: (HCl salt)77-80° C.; 1H NMR (free base, 300 MHz, CDCl₃) δ1.3-2.0(5H, m), 2.0-2.5 (4H, m), 2.5-3.3 (5H, m), 3.7 (3H, s), 3.4-4.8 (3H, m),3.8-4.9 (5H, m), 7.0 (2H, m), 7.3 (4H, m); MS (FAB) 632 (M+H)⁺; Anal.Calcd for C₃₀H₃₃F₆N₃O₄.

EXAMPLE 1lMethyl-4-[(3,4-dichlorophenyl)acetyl]-3-(R)-[(2-(S)-pyrrolidinemethanol)methyl]-1-piperazinecarboxylatehydrochloride

The compound was prepared by aq. LiOH hydrolization of 1k; mp: (HClsalt)135-138° C.; ¹H NMR (free base, 300 MHz, CDCl₃) δ1.6-1.8 (4H, m),3.7 (3H, s), 2.0-4.1 (15H, m), 4.3-4.8 (2H, m), 7.0 (1H, m), 7.3 (1H,m); MS (FAB) 444 (M+H)⁺; Anal. Calcd. for C₂₀H₂₇Cl₂N₃O₄.HCl.H₂O: C,48.16; H, 6.06; N, 8.42. Found: C, 48.64; H, 6.05; N, 8.45.

EXAMPLE 1mMethyl-4-[(2-nitro-4-α,α,α-trifluoromethylphenyl)acetyl]-3-(R,S)-[(2-(S)-pyrrolidinemethanol)methyl]-1-piperazinecarboxylatehydrochloride

The compound was prepared by aq. LiOH hydrolization ofmethyl-4-[(2-nitro-4-α,α,α-trifluoromethylphenyl)acetyl]-3-(R,S)-[(2-(S)pyrrolidinemethyl-2′-nitro-4′-α,α,α-trifluoromethylphenyl)acetate)methyl]-1-piperazinecarboxylate;mp: (HCl salt)136-140° C.; ¹H NMR (free base, 300 MHz, CDCl₃) δ1.6-1.9(3H, m), 3.7 (3H, d), 2.1-3.6 (12H, m), 3.9-4.9 (6H, m), 7.4 (1H, d),7.8 (1H, d), 8.3 (1H, s); MS (FAB) 489 (M+H)⁺; Anal. Calcd. forC₂₁H₂₇F₃N₃O₆.HCl: C, 48.05,; H, 5.38; N, 10.67. Found: C, 47.81; H,5.27; N, 10.49.

EXAMPLE 1nMethyl-4-[(4-methylsulphonylphenyl)acetyl]-3-(R,S)-[(2-(S)-pyrrolidinemethyl-4′-methylsulphonylphenylacetate)methyl]-1-piperazinecarboxylatehydrochloride

The compound was prepared by coupling of 4-methylsulphonylphenylaceticacid withmethyl-3-(R,S)-[(2-(S)-pyrrolidinemethanol)methyl]-1-piperazinecarboxylate;mp: (HCl salt)133-135° C.; ¹H NMR (free base, 300 MHz, CDCl₃) δ1.4-2.5(5H, m), 3.0 (3H, s), 2.6-3.3 (8H, m), 3.4-4.9 (15H, m), 7.4 (4H, m),7.9 (4H, m); MS (FAB) 650 (M+H)⁺; Anal. Calcd. forC₃₀H₃₉S₂N₃O₉.HCl.0.75NH₄Cl: C, 49.61; H, 5.97; N, 7.23. Found: C, 50.07;H, 6.17; N, 7.26.

EXAMPLE 1oMethyl-4-[(4-methylsulphonylphenyl)acetyl]-3-(R,S)-[(2-(S)-pyrrolidinemethanol)methyl]-1-piperazinecarboxylatehydrochloride

The compound was prepared by aq. LiOH hydrolization of compound 1n; mp:(HCl salt)130-135° C.; ¹H NMR (free base, 300 MHz, CDCl₃) δ1.6-1.9 (4H,m), 2.1-2.5 (2H, m), 2.5-3.4 (7H, m), 3.0 (3H, s), 3.4-4.2 (6H, m), 3.7(3H, m), 4.2-5.0 (2H, m), 7.5 (2H, m), 7.9 (2H, m); MS (FAB) 454 (M+H)⁺;Anal. Calcd. for C₂₁H₃₁SN₃O₆.HCl.H₂O: C, 49.65; H, 6.75; N, 8.27. Found:C, 50.19; H, 6.77; N, 8.26.

EXAMPLE 1pMethyl-4-[(2-amino-4-α,α,α-trifluoromethylphenyl)acetyl]-3-(R,S)-[(2-(S)-pyrrolidinemethanol)methyl]-1-piperazinecarboxylatehydrochloride

The compound was prepared by Pd catalyzed hydrogenation of compound 1m;mp: (HCl salt)140-143° C.; ¹H NMR (free base, 300 MHz, CDCl₃) δ1.7-3.3(12H, m), 3.7 (3H, s), 3.3-4.3 (11H, m), 6.9 (2H, m), 7.1 (1H, m); MS(FAB) 459 (M+H)⁺; Anal. Calcd. for C₂₁H₂₉F₃N₄O₄.2HCl.CH₃OH: C, 46.90; H,6.26; N, 9.94. Found: C, 46.9; H, 6.14; N, 9.93.

EXAMPLE 1qMethyl-4-[(3,4-dichlorophenyl)acetyl]-2-(R,S)-[3-(S)-(3′,4′-dichlorephenylacetate)-1-(pyrrolidinyl)methyl]-1-piperazinecarboxylatehydrochloride

The compound was prepared by coupling of 3,4-dichlorophenylacetic acidwith methyl-3-(R,S)-[3-(S)-hydroxy-1-(pyrrolidinyl)methyl]-1-piperazinecarboxylate; mp: (HCl salt)125-128° C.; ¹H NMR (free base, 200 MHz,CDCl₃) δ1.9-3.1 (9H, m), 3.4-3.8 (8H, m), 4.0-4.2 (3H, m), 4.5-5.2 (3H,m), 7.1(2H, m), 7.4 (4H, m); MS (FAB) 618 (M+H)⁺; Anal. Calcd forC₂₇H₂₉Cl₄N₃O₅.HCl: C, 49.60; H, 4.62; N, 6.43. Found: C, 49.39; H, 4.65;N, 6.44.

EXAMPLE 1r4-Acetyl-1-[3-(N-methylsulfonamido)phenyl]acetyl-2-(R,S)-[(1-pyrrolidinyl)methyl]piperazinehydrochloride

The compound was prepared by methylsulphonylation of4-acetyl-1-[3-amino)phenyl]acetyl-2-(R,S)-[(1-pyrrolidinyl)methyl]piperazineas clear oil, the dihydrochloride salt was prepared from 1M etherialHCl; mp: (HCl salt)140° C.(dec.); ¹H NMR (free base, 200 MHz, CDCl₃)δ1.5-1.7 (4H, m), 1.8-3.1 (13H, m), 3.4-4.9 (9H, m), 6.5 (2H, m), 7.0(2H, m); MS (FAB) 423 (M+H)⁺. Anal. Calcd. for C₂₀H₃₀N₄O₄S.HCl.NH₄Cl: C,46.87; H, 6.88; N, 13.67. Found: C, 44.83; H, 7.18; N, 13.16.

EXAMPLE 1s4-Acetyl-1-[(2-acetylamidophenyl)acetyl]-2-(R,S)-[(1-pyrrolidinyl)methyl]piperazinehydrochloride

The compound was prepared by acetylation of4-acetyl-1-[(2-aminophenyl)acetyl]-2-(R,S)-[(1-pyrrolidinyl)methyl]piperazine;mp: (HCl salt)173° C.(dec.); ¹H NMR (free base, 200 MHz, CDCl₃) δ1.3-1.8(6H, m), 2.0 (3H, s), 2.1 (3H, 3), 2.2-3.4 (8H, m), 3.6-4.8 (6H, m),6.9-7.2 (3H, m), 7.8 (1H, m); MS (FAB) 387 (M+H)⁺; Anal. Calcd. forC₂₁H₃₀N₄O₃.HCl.2H₂O: C, 54.95; H, 7.69; N, 12.21. Found: C, 54.53; H,6.91; N, 11.92.

EXAMPLE 1t4-Acetyl-1-[(4-acetylamidophenyl)acetyl]-2-(R,S)-[(1-pyrrolidinyl)methyl]piperazinehydrochloride

The compound was prepared by acetylation of4-acetyl-1-[(4-aminophenyl)acetyl]-2-(R,S)-[(1-pyrrolidinyl)methyl]piperazine;mp: (HCl salt)165° C.(dec.); ¹H NMR (free base, 200 MHz, CDCl₃) δ1.5-1.7(5H, m), 1.9-2.1 (6H, m), 2.2-3.1 (8H, m), 3.5-4.7 (6H, m), 7.0 (2H, m),7.4 (2H, m); MS (FAB) 387 (M+H)⁺; Anal. Calcd for C₂₁H₃₀O₃N₄.HCl.H₂O: C,57.20; H, 7.54; N, 12.71. Found: C, 57.05; H, 7.31; N, 12.74.

EXAMPLE 1u4-Acetyl-1-[(4-methylsulfonylphenyl)acetyl]-2-(R,S)-[3-(S)-(4′-methylsulfonylphenylacetate)-1-(pyrrolidinyl)methyl]piperazine hydrochloride

The compound was prepared by coupling of 4-methylsulfonylphenylaceticacid with4-acetyl-2-(R,S)-[3-(S)-hydroxy-1-(pyrrolidinyl)methyl]piperazine; mp:(HCl salt)160-163° C.; ¹H NMR (free base, 200 MHz, CDCl₃) δ1.7-2.2 (7H,m), 2.3-3.2 (12H, m), 3.0 (6H, s), 3.5-4.1 (8H, m), 4.4-5.2 (4H, m), 7.4(4H, m), 7.8 (4H, m); MS (FAB) 620(M+H)⁺; Anal. Calcd forC₂₉H₃₇S₂N₃O₈.HCl: C, 53.00; H, 5.98; N, 6.39. Found: C, 52.26; H, 6.00;N, 6.37.

EXAMPLE 1v4-Acetyl-1-[(4-α,α,α-trifluoromethylphenyl)acetyl]-2-(R,S)-[3-(S)-(4′-α,α,αtrifluoromethylphenyl acetate)-1-(pyrrolidinyl)methyl]piperazinehydrochloride

The compound was prepared by coupling of 4-α,α,α-trifluoromethyphenylacetic acid with4-acetyl-2-(R,S)-[3-(S)-hydroxy-1-(pyrrolidinyl)methyl]piperazine; m.p:(HCl salt)134-136° C.; ¹H NMR (free base, 200 MHz, CDCl₃) δ1.6-3.2 (15H,m), 3.4-4.1 (5H, m), 4.3-5.2 (3H, m), 7.3 (4H, m), 7.5 (4H, m); MS (FAB)599 (M+H)⁺; Anal. Calcd for C₂₉H₃₁F₆N₃O₄.HCl.0.5NH₄Cl: C, 52.55; H,5.17; N, 7.40. Found: C, 52.05; H, 5.56; N, 7.90.

EXAMPLE 1w4-Acetyl-1-[(3,4-dichlorophenyl)acetyl]-2-(R,S)-[3-(S)-(3′,4′-dichlorophenylacetate)-1-(pyrrolidinyl)methyl]piperazine hydrochloride

The compound was prepared by coupling of 3,4-dichlorophenylacetic acidwith 4-acetyl-2-(R,S)-[3-(S)-hydroxy-1-(pyrrolidinyl)methyl]piperazine;mp: (HCl salt)122-125° C.; ¹H NMR (free base, 200 MHz CDCl₃) δ1.6-1.9(3H, m), 2.1 (3H, s), 2.1-3.9 (14H, m), 4.0-5.3 (3H, m), 7.1 (2H, m),7.4 (4H, m); MS (FAB) 602 (M+H)⁺; Anal. Calcd for C₂₇H₂₉Cl₄N₃O₄.HCl: C,50.84; H, 4.74; N, 6.59. Found: C, 49.33; H, 4.76; N, 6.85.

EXAMPLE 1x4-Acetyl-1-[(3,4-dichlorophenyl)acetyl]-2-(R,S)-[(2-(S)-pyrrolidinemethyl-3′,4′dichlorophenylacetate)methyl]piperazine hydrochloride

The compound was prepared by coupling of 3,4-dichlorophenylacetic acidwith 4-acetyl-2-(R,S)-[(2-(S)pyrrolidinemethanol)methyl]piperazine; mp:(HCl salt)107-110° C.; ¹H NMR (free base, 300 MHz, CDCl₃) δ1.5-2.0 (3H,m), 2.0-2.2 (3H, d), 2.2-3.3 (9H, m), 3.5-4.1 (8H, m), 4.4-4.9 ((2H, m),7.1 (2H, m), 7.4 (4H, m); MS (FAB) 616 (M+H)⁺; Anal. Calcd. forC₂₈H₃₁Cl₄N₃O₄.HCl.NH₄Cl: C, 47.68; H, 5.14; N, 7.94. Found: C, 47.80; H,5.38; N, 9.05.

EXAMPLE 1y4-Acetyl-1-[(4-trifluoromethylphenyl)acetyl]-2-(R,S)-[2-(S)-pyrrolidinemethyl-4′-trifluoromelthylphenylacetate)methyl]piperazinehydrochloride

The compound was prepared by coupling of 3,4-dichlorophenylacetic acidwith 4-acetyl-2-(R,S)-[(2-(S)-pyrrolidinemethanol)methyl]piperazine; mp:(HCl salt)110-113° C.; ¹H NMR (free base, 300 MHz, CDCl₃) δ1.5-3.3 (12H,m), 2.1 (3H, s), 3.5-4.1 (9H, m), 4.3-4.9 (1H, m), 7.3 (4H, m), 7.5 (4H,m); MS (FAB) 614 (M+H)⁺; Anal. Calcd for C₃₀H₃₃F₆N₃O₄.HCl.0.5NH₄Cl: C,53.24; H, 5.36; N, 7.24. Found: C, 53.86; H, 5.45; N, 6.91.

EXAMPLE 1z4-Acetyl-1-[(3,4-dichlorophenyl)acetyl]-2-(R,S)-[(2-(S)-pyrrolidinemethanol)methyl]piperazinehydrochloride

The compound was prepared by aq. LiOH hydrolization of compound 1x; mp:(HCl salt)123-125° C.; ¹H NMR (free base, 300 MHz, CDCl₃) δ1.6-2.0 (4H,m), 2.1 (3H, m), 2.2-3.4 (10H, m), 3.4-4.0 (5H, m), 4.4-5.0 (2H, m), 7.1(2H, m), 7.4 (2H, m); MS (FAB) 428 (M+H)⁺; Anal. Calcd. forC₂₀H₂₇Cl₂N₃O₃.HCl: C, 51.68; H, 6.07; N, 9.04. Found: C, 49.84; H, 6.08;N, 9.03.

EXAMPLE 1aa4-Acetyl-1-[(4-methylsulphonylphenyl)acetyl]-2-(R,S)-[(2-(S)-pyrrolidinemethyl-4′-methylsulphonylphenylacetate)methyl]piperazinehydrochloride

The compound was prepared by coupling of 4-methylsulphonylphenylaceticacid with4-acetyl-2-(R,S)-[(2-(S)-pyrrolidinemethanol)methyl]piperazine; mp: (HClsalt) 145-148° C.; ¹H NMR (free base, 300 MHz, CDCl₃) δ1.5-2.0 (3H, m),2.1 (3H, m), 3.0 (6H, s), 2.5-3.3 (9H, m), 3.6-4.2 (9H, m), 4.5 (1H, m),7.5 (4H, m), 7.9 (4H, m); MS (FAB) 634 (M+H)⁺; Anal. Calcd. forC₃₀H₃₉S₂N₃O₈.HCl.0.25NH₄Cl: C, 52.71; H, 6.05; N, 6.66. Found: C, 52.02;H, 6.19; N, 6.59

EXAMPLE 1bb4-Acetyl-1-[(4-methylsulphonylphenyl)acetyl]-2-(R,S)-[(2-(S)-pyrrolidinemethanol)methyl]piperazinehydrochloride

The compound was prepared by aq. LiOH hydrolization of compound 1aa; mp:(HCl salt)138-140° C.; ¹H NMR (free base, 300 MHz, CDCl₃) δ1.6-2.0 (4H,m), 2.1 (3H, m), 2.2-3.0 (5H, m), 3.1 (3H, s), 3.1-4.0 (10H, m), 4.4-5.0(2H, m), 7.5 (2H, m), 7.9 (2H, m); MS (FAB) 438 (M+H)⁺; Anal. Calcd. forC₂₁H₃₁SN₃O₅.HCl.H₂O: C, 51.26; H, 6.96; N, 8.54. Found: C, 50.36; H,6.92; N, 8.90.

EXAMPLE 1cc4-Acetyl-1-[(4-trifluoromethylphenyl)acetyl]-2-(R,S)-[(2-(S)-pyrrolidinemethanol)methyl]piperazinehydrochloride

The compound was prepared by aq. LiOH hydrolization of compound 1y; mp:(HCl salt)123-125° C.; ¹H NMR (free base, 300 MHz, CDCl₃) δ1.6-2.2 (4H,m), 2.1 (3H, s), 2.2-4.0 (15H, m), 4.5-5.0 (2H, m), 7.4 (2H, m), 7.6(2H, m); MS (FAB) 428 (M+H)⁺; Anal. Calcd for C₂₁H₂₈F₃N₃O₃.HCl.NH₄Cl: C,48.75; H, 6.43; N, 10.83. Found: C, 47.46; H, 6.04; N, 12.40.

EXAMPLE 1dd4-Formyl-1-[(2-N-methysulfamylphenyl)acetyl]-2-(R,S)-[(1-pyrrolidinyl)methyl]piperazinehydrochloride

The compound was prepared by coupling of 2-(N-methylaminosulfonyl)phenylacetic acid with 4-formyl-2-(R,S)-[(1-pyrrolidinyl)methyl]piperazine;m.p.: (HCl salt) 150° C.(dec.); ¹H NMR (free base, 200 Mz, CDCl₃) δ1.7(4H, m), 2.2-3.2 (11H, m), 3.4-4.0 (4H, m), 4.2-5.4 (4H, m), 7.0 (1H,m), 7.4 (2H, m), 7.6 (1H, m), 8.0 (1H, m); MS (FAB) 409 (M+H)⁺; Anal.Calcd for C₁₉H₂₈O₄N₄S.HCl.0.5NH₄Cl: C, 48.38; H, 6.62; N, 13.36. Found:C, 48.08; H, 6.46; N, 13.33.

EXAMPLE 1ee4-Carbonylimidazole-1-[(3,4-dichlorophenyl)acetyl]-2-(R)-[(1-pyrrolidinyl)methyl]piperazinehydrochloride

The compound was prepared by coupling of 1,1′-carbonyldiimidazole with1-[(3,4-dichlorophenyl)acetyl]-2-(R)-[(1-pyrrolidinyl)methyl]piperazine;mp: (HCl salt)148° C.(dec.); ¹H NMR (free base, 200 MHz, CDCl₃) δ1.5-1.7(4H, m), 2.1-2.5 (5H, m), 2.6-3.4 (4H, m), 3.5-4.8 (7H, m), 6.9-7.4 (4H,m), 8.0 (1H, m); MS (FAB) 450 (M+H)⁺; Anal. Calcd forC₂₁H₂₅Cl₂N₅O₂.2HCl.H₂O: C, 46.60; H, 5.40; N, 12.94. Found: C, 45.41; H,5.33; N, 12.73.

EXAMPLE 1ff4-Allyl-1-[(3,4-dichlorophenyl)acetyl]-2-(R)-[(1-pyrrolidinyl)methyl]piperazinehydrochloride

The compound was prepared by coupling of allyl bromide with1-[(3,4-dichlorophenyl)acetyl]-2-(R)-[(1-pyrrolidinyl)methyl]piperazinein 81% yield; mp: (HCl salt)157-160° C.; ¹H NMR (free base, 200 MHz,CDCl₃) δ1.4-2.0 (6H, m), 2.3-3.0 (6H, m), 3.1-3.8 (4H, m), 4.3-4.8 (1H,m), 4.9-5.1 (2H, m), 5.7-5.9 (1H, m), 7.0-7.3 (3H, m); MS (FAB) 396(M+H)⁺; Anal. Calcd for C₂₀H₂₇Cl₂N₃O.2HCl: C, 51.19; H, 6.23; N, 8.95.Found: C, 50.89; H, 6.42; N, 8.65.

EXAMPLE 1gg4-Acetyl-1-[(2-pyridyl)acetyl]-2-(R,S)-[(1-pyrrolidinyl)methyl]piperazinehydrochloride

The compound was prepared by coupling of 2-pyridylacetic acid with4-acetyl-2-(R,S)-[(1-pyrrolidinyl)methyl]piperazine; mp: (HCl salt)127-130° C.; ¹H NMR (free base, 200 MHz, CDCl₃) δ1.4-1.7 (4H, m), 2.0(3H, s), 2.2-3.2 (9H, m), 3.4-4.8 (6H, m), 6.8-7.5 (3H, m), 8.4 (1H, m);MS (FAB) 331 (M+H)⁺; Anal. Calcd. for C₁₈H₂₆N₄O₂.2HCl.0.5NH₄Cl: C,50.27; H, 7.03; N, 14.65. Found: C, 50.86; H, 6.47; N, 15.79.

EXAMPLE 1hh4-Formyl-1-[(2-pyridyl)acetyl]-2-(R,S)-[(1-pyrrolidinyl)methyl]piperazinehydrochloride

The compound was prepared by coupling of 2-pyridinylacetic acid with4-formyl-2-(R,S)-[(1-pyrrolidinyl)methyl]piperazine; mp: (HCl salt)125-128° C.; ¹H NMR (free base, 200 MHz, CDCl₃) δ1.5-1.7 (4H, m),2.1-3.6 (10H, m), 3.7-4.9 (5H, m), 6.9-7.3 (2H, m), 7.6 (1H, m), 8.0(1H, m), 8.6 (1H, m); MS (FAB) 317 (M+H)⁺; Anal. Calcd. forC₁₇H₂₄N₄O₂.2HCl.NH₄Cl: C, 46.11; H, 6.83; N, 15.82. Found: C, 46.37; H,6.51; N, 16.35.

EXAMPLE 1iiMethyl-4-[(3,4-dichlorophenyl)acetyl]-3-(S)-[(2-(S)-pyrrolidinemethanol)methyl]-1-piperazinecarboxlatehydrochloride

The compound was prepared by aq. LiOH hydrolization of 1k; mp: (HClsalt)137-140° C.; ¹H NMR (free base, 300 MHz, CDCl₃) δ1.5-2.0 (4H, m),3.7 (3H, s), 2.1-3.7 (14H, m), 3.8-4.9 (3H, m), 7.1 (1H, m), 7.3 (2H,m); MS (FAB) 444 (M+H)⁺; Anal. Calcd. for C₂₀H₂₇Cl₂N₃O₄.HCl.0.5NH₄Cl: C,47.33; H, 5.96; N, 9.66. Found: C, 47.55; H, 6.11; N, 9.39.

EXAMPLE 1jj4-Methanesulfonyl-1-[3,4-dichlorophenyl)acetyl]-2-(R,S)-[3-(S)-methanesulfonate-1-(pyrrolidinyl)methyl]piperazinehydrochloride

The compound was prepared from1-[(3,4-dichlorophenyl)acetyl]-2-[(3-hydroxy-1-pyrrolidinyl)methyl]piperazinedihydrochloride¹ (0.25 g, 0.56 mmol), methanesulfonyl chloride(0.43 mL,5.56 mmol), triethylamine (2.3 mL, 16.53 mmol) and CH₂Cl₂ (20 mL) at 0°C. for 6 h. After dilution with saturated NaHCO₃ solution (20 mL) andwashed with water (20 mL). Then, dried over Mg₂SO₄. The compound waspurified by flash chromatography on silica gel, eluting withCH₂Cl₂:CH₃OH:28%NH₄OH(99:1:2) to give the desired product as a free base(0.28 g; 94% yield) and a hydrochloride salt was generated(0.067 g; mp.130-132° C.; ¹H NMR (free base, 300 MHz, CDCl₃) δ2.10(m, 1H), 2.29(m,1H), 2.59(m, 4H), 2.89 (s. 3H),3.01 (s, 3H), 3.2-3.5(m,2H), 3.60-3.9(m,4H),4.90 (m, 1H), 5.15(m, 1H,)7.12(d, J=8.2 Hz, 1H), 7.43 (d, J=8.3 Hz,2H); MS (FAB) 528 (M+H)⁺; Anal. Calcd. for C₁₉H₂₇Cl₂N₃O₆S₂.HCl: C,40.40; H, 5.00; N, 7.44. Found: C, 40.29; H, 5.07; N, 7.04.

EXAMPLE 1kk4-Methylsulphonyl-1-[(3,4-dichlorophenyl)acetyl]-2-(R,S)-[3-(S)-(3′,4′dichlorophenylacetate)-1-(pyrrolidinyl)methyl]piperazine hydrochloride

The compound was prepared by coupling of 3,4-dichlorophenylacetic acidwith4-methylsulphonyl-2-(R,S)-[3-(S)-(hydroxy)-1-(pyrrolidinyl)methyl]piperazine;mp: (HCl salt)145-148° C.; ¹H NMR (freebase, 200 MHz, CDCl₃) δ1.5-1.9(2H, m), 2.2-3.0 (7H, m), 2.7 (3H, s),3.5-4.0 (8H, m) 4.9-5.2 (3H, m),7.1 (2H, m), 7.4 (4H, m); MS (FAB) 638(M+H)+; Anal. Calcd. forC₂₆H₂₉Cl₄N₃O₅S.HCl.0.5NH₄Cl: C, 44.52; H,4.60; N, 7.00. Found: C, 45.66;H, 4.72; N, 7.61.

EXAMPLE 1ll4-Methylsulphonyl-1-[(3,4-dichlorophenyl)acetyl]-2-(RS)-[(3-(S)-hydroxy-1-pyrrolidinyl)methyl]piperazinehydrochloride

The compound was prepared by aq. LiOH hydrolization of 1kk; mp: (HClsalt)150-153° C.; ¹H NMR (free base, 200 MHz, CDCl₃) δ8 1.5-2.3(4H, m),2.4-3.2 (7H,m), 2.8 (3H, s), 3.4-4.0 (5H, m), 4.5-5.2 (3H, m), 7.1(1H,m), 7.4 (2H, m); MS (FAB) 450 (M+H)+; Anal. Calcd. ForC₁₈H₂₅Cl₂N₃O₄S.HCl.0.25NH₄Cl: C, 43.22; H, 5.44; N, 9.10. Found:C,43.23; H, 5.16; N, 9.8

EXAMPLE 1mm4-Methylsulphonyl-1-[(4-α,α,α-triflouromethylphenyl)acetyl]-2-(R,S)-[3-(S)-(4′-α,α,α-triflouromethylphenylacetate)-1-(pyrrolidinyl)methyl]piperazine hydrochloride

The compound was prepared by coupling of 4-(a,a,a-triflouromethyl)phenylacetic acid with4-methylsulphonyl-2-(R,S)-[3-(S)-hydroxy-1-(pyrrolidinyl)methyl]piperazine;mp:(HCl salt) 120-123° C.; ¹H NMR (free base, 200 MHz, CDCl₃) δ1.8-2.2(4H,m), 2.4-3.3 (8H, m), 2.7 (3H, s), 3.6-4.0 (6H, m), 4.8-5.2 (2H, m),7.4 (4H,m), 7.6 (4H, m); MS (FAB) 636 (M+H)+; Anal. Calcd. ForC₂₈H₃₁F₆N₃O₅S.HCl: C, 50.04; H, 4.80; N, 6.25. Found: C, 50.34; H,4.80;N, 6.09.

EXAMPLE 1nn4-Methylsulphonyl-1-[(4-α,α,α-triflouromethylphenyl)acetyl]-2-(R,S)-[(3-(S)-hydroxy-1-pyrrolidinyl)methyl]piperazinehydrochloride

The compound was prepared by aq. LiOH hydrolization of 1 mm; mp: (HClsalt) 145° C.(dec.); ¹H NMR (free base, 200 MHz, CDCl₃) δ1.5-2.1 (3H,m), 2.3-3.4 (9H, m), 2.8 (3H, s), 3.7-4.0 (5H, m), 4.3-5.0 (2H,m), 7.4(2H, m), 7.6 (2H, m); MS (FAB) 450 (M+H)+; Anal. Calcd. forC₁₉H₂₆F₃N₃O₄S.HCl: C, 46.96; H, 5.60; N, 8.65. Found: C, 46.45; H, 5.66;N, 8.69.

EXAMPLE 1oo4-Acetyl-1-[(3,4-dichlorophenyl)acetyl]-2-(S)-[(3′-(S-hydroxy-1-pyrrolidine)methyl]piperazinehydrochloride

The compound was prepared by coupling of 3,4dichlorophenylacetic acidwith 4-acetyl-2-(R,S)-[(3′-(S)-hydroxypyrrolidine)methyl]piperazine.Then, this racemic mixture was separated on a Chiralpak AD column using100% acetonitrile as the eluant. Then, from the 2-(S), 3′-(S) enantiomera HCl salt was generated (1.0 gm.); mp: (HCl salt)130-135° C.; [a]²⁰+25.56° (0.85%; w/v MeOH). ¹H NMR (free base, 300 MHz, CDCl₃) δ1.74 (1H,m), 2.13 (3H, s), 2.2(1H, m), 2.3-3.2 (10H, m), 3.45-3.71 (3H, m), 4.11(1H, d) 4.21-4.74(2H, m), 4.55((1H, m), 7.10 (1H, J=8.25 Hz, d), 7.41(2H, J=8.28 Hz, d); MS (FAB) 414 (M+H)⁺; Anal. Calcd. forC₁₉H₂₅Cl₂N₃O₃.HCl.0.5H₂O: C, 49.65; H, 5.77; N, 8.91. Found: C, 49.58;H, 5.65; N, 9.13.

EXAMPLE 1pp4-Acetyl-1-[(3,4-dichlorophenyl)acetyl]-2-(R)-[(3′-(R)-hydroxy-1-pyrrolidine)methyl]piperazinehydrochloride

The compound was prepared by coupling of 3,4-dichlorophenylacetic acidwith 4-acetyl-2-(R,S)-[(3′-(R)-hydroxy-1-pyrrolidine)methyl]piperazine.Then, this racemic mixture was separated on a Chiralpak AD column using100% acetonitrile as the eluant. Then, from the 2-(R), 3′-(R) enantiomera HCl salt was generated (0.9 gm); mp: (HCl salt)130-135° C.; [a]²⁰−30.49° (0.88%; w/v MeOH). ¹H NMR (free base, 300 MHz, CDCl₃) δ1.74 (1H,m), 2.13 (3H, s), 2.2(1H, m), 2.3-3.2 (10H, m), 3.45-3.71 (3H, m), 4.11(1H, d) 4.21-4.74(2H, m), 4.55((1H, m), 7.10 (1H, J=8.25 Hz, d), 7.41(2H, J=8.28 Hz, d); MS (FAB) 414 (M+H)⁺; Anal. Calcd. forC₁₉H₂₅Cl₂N₃O₃.HCl: C, 50.62; H, 5.81; N, 9.32. Found: C, 49.94; H, 5.84;N, 8.97.

EXAMPLE 1qq4-Acetyl-1-[(3,4dichlorophenyl)acetyl]-2-(S)-[(3′-(R)-hydroxy-1-pyrrolidine)methyl]piperazinehydrochloride

The compound was prepared by coupling of 3,4-dichlorophenylacetic acidwith 4-acetyl-2-(R,S)-[(3′-(R)-hydroxy-1-pyrrolidine)methyl]piperazine.Then, this racemic mixture was separated on a Chiralpak AD column using100% acetonitrile as the eluant. Then, from the 2-(S), 3′-(R) enantiomera HCl salt was generated (1.05 gm); mp: (HCl salt)130-135° C.; [a]²⁰+28.8° (0.75%; w/v MeOH). ¹H NMR (free base, 300 MHz, CDCl₃) δ1.74 (1H,m), 2.13 (3H, s), 2.2(1H, m), 2.3-3.2 (10H, m), 3.45-3.71 (3H, m), 4.11(1H, d) 4.21-4.74(2H, m), 4.55((1H, m), 7.10 (1H, J=8.25 Hz, d), 7.41(2H, J=8.28 Hz, d); MS (FAB) 414 (M+H)⁺; Anal. Calcd. forC₁₉H₂₅Cl₂N₃O₃.HCl: C, 50.62; H, 5.81; N, 9.32. Found: C, 50.19; H, 5.86;N, 9.06.

Compounds of Formula II

General Procedure for DCC/pyr Coupling

With stirring at 25° C. under N₂, DCC (2.06 eq) and CH₂Cl₂ were added toa mixture of the acid (2 eq) and pyridine (2.06 eq) in CH₂Cl₂. After 1-2min, a solution of the amine (1 eq) in CH₂Cl₂ was added, and the mixturewas stirred at 25° C. under N₂ overnight. The final concentration of themixture is around 0.1-0.3 mM with respect to the amine. Sat'd. NaHCO₃ (2mL) was added to destroy excess active esters before the mixture wasfiltered through celite, and the DCU was washed with CH₂Cl₂. Thefiltrate was then partitioned between sat'd NaHCO₃ and CH₂Cl₂, which wasdried (Na₂SO₄), filtered through celite, and evaporated. Toluene wasadded to azeotrope off pyridine before the crude product waschromatographed and converted to the HCl salt.

Compounds having the following structures were prepared:

(±)-3, ADL-01-0017-2, X=—OMe, R₁=—H, R₂=3,4-Cl₂-phenyl

(±)-4, ADL-01-0018-0, X=—OH, R₁=—H, R₂=3,4-Cl₂-phenyl

(±)-5, ADL-01-0019-8, X=—OCH₂CO₂H, R₁=—H, R₂=3,4-Cl₂-phenyl

(±)-6, ADL-01-0020-6, X=—OMe, R₁=R₂=phenyl

(±)-7, ADL-01-0021-4, X=—OH, R₁=R₂=phenyl

(±)-8; ADL-01-0029-7, X=—NO₂, R₁=—H, R₂=2-NO₂-4,5-Cl₂-phenyl

(±)-9, ADL-01-0031-3, X=—NO₂, R₁=—H, R₂=3,4-Cl₂-phenyl

(±)-10, ADL-01-0032-1, X=—NH₂, R₁=—H, R₂=3,4-Cl₂-phenyl

(±)-11, ADL-01-0034-7, X=—NO₂, R₁=—H, R₂=4-methylsulfonylphenyl

(±)-12, ADL-01-0037-0, X=—N(CH₂CO₂tBu)₂, R₁=—H, R₂=3,4-Cl₂-phenyl

(±)-13, ADL-01-0044-6, X=—N(CH₂CO₂H)₂, R₁=—H, R₂=3,4-Cl₂-phenyl

(±)-14, ADL-01-0052-9, X=—N(CH₂CO₂Et)₂, R₁=—H R₂=3,4-Cl₂-phenyl

(±)-15, ADL-01-0053-7, X=—NHPO₃Et₂, R₁=—H, R₂=3,4-Cl₂-phenyl

(±)-16, ADL-01-0070-1, X=—NH(CH₂)₂PO₃Et₂, R₁=—H, R₂=3,4-Cl₂-phenyl

Intermediates (±)-1 and (±)-2 were prepared via reported methods fromthe appropriate starting materials.⁵ Compounds (±)-3 and (±)-4 are knowncompounds prepared via reported methods.⁵ Compounds (±)-5 through (±)-16were prepared by DCC coupling of either (±)-1 or (±)-2 to an arylaceticacid followed by demethylation or reduction to allow peripheralization.

Ref.

(5) Rajagopalan, P. et al. Bioorg. Med. Chem. Letters 1992, 2, 721-726.

Intermediates 17 and 18 were prepared via known methods from6-methoxy-1-tetralone and 1-tetralone, respectively. Intermediates 17and 18 were coupled to 3,4-dichlorophenylacetic acid to produce (±)-19and (±)-20.

Intermediates (±)-21 and (±)-23 were prepared via similar chemistry from1-benzosuberone and (±)-trans-2-bromo-1-indanol.1 Compounds (±)-22,(±)-25 (Niravoline),⁶ and (±)-27 are known compounds prepared viareported chemistry.¹ Compounds (±)-24 through (±)-29 were prepared byDCC coupling to the appropriate arylacetic acid.

Ref.

(6) Bellissant, E. et al. J. Pharmacol. Exp. Ther. 1996, 278, 232-242.

Representative examples of formula II follow.

EXAMPLE 332-{7-[(±)-trans-1-(N-3,4-dichlorophenylacetamido-N-methylamino)-2-(1-pyrrolidinyl)-1,2,3,4-tetrahydronaphthoxy]}aceticacid ((±)-5, ADL-01-0019-8)

With stirring at 25° C. under N₂, t-butyl bromoacetate (0.35 mL, 2.38mmol) was added to a mixture of (±)-4 (0.688 g, 1.59 mmol) and K₂CO₃(0.5 g, 3.6 mmol) in DMF (8 mL), and the mixture was stirred at 25° C.under N₂ overnight before the mixture was. evaporated under high vacuumThe residue was partitioned between sat'd NaHCO₃ and CH₂Cl₂ (2×100 mL),which was dried (Na2SO₄), filtered through celite, and evaporated. Thet-butyl ester intermediate was flash column chromatographed twiceeluting with CH₂Cl₂:2% NH₃:2% MeOH and CH₂Cl₂:2% NH₃:1% MeOH,respectively. The t-butyl ester was then deprotected in a mixture of THF(4 mL) and conc. HCl (2 mL) with stirring at 25° C. overnight and at 50°C. for 1 h before the mixture was evaporated. The residue was thendissolved in a mixture of trifluoroacetic acid (2 mL), 4 N HCl (2 mL),and anisole (1 drop), and stirred at 25° C. for 2.5 days before themixture was evaporated. The oily residue was triturated with Et₂O andsonicated to yield (±)-5.HCl (0.259 g, 31%): m.p. (HCl salt) 138° C.(dec); ¹H NMR (HCl salt, DMSO-d₆) δ1.7-2.1 (br s, 4H, —CH₂CH₂—), 2.2-4.8(complex, 13H, 6 —CH₂— and 1 —CH—), 2.79 (s, 3H, —NCH₃), 5.98 (d, J=10.3Hz, 1H, —CH—), 6.40 (s, 1H, aromatic), 6.82 (m, 1H, aromatic), 7.12 (d,J=8.2 Hz, 1H, aromatic), 7.39 (d, J=8.3 Hz, 1H, aromatic), 7.63 (m, 2H,aromatic). MS (FAB) m/z 491. Anal. (C, H, N) C₂₅H₂₈N₂O₄Cl₂.HCl.

EXAMPLE 342,2-Diphenyl-N-methyl-N-[(±)-trans-2-(1-pyrrolidinyl)-7-methoxy-1,2,3,4-tetrahydronaphth-1-yl]acetamide((±)-6, ADL-01-0020-6)

ADL-01-0020-6 was prepared via the general DCC/pyr coupling method from(+)-1 (1.453 g, 5.58 mmol), diphenylacetic acid (2.369 g, 11.16 mmol),DCC (2.373 g, 11.50 mmol), and pyridine (0.93 mL, 11.5 mmol). Theproduct was flash column chromatographed eluting with CH₂Cl₂:2% NH₃:1%MeOH before it was converted to the HCl salt with 1.0 M HCl in Et₂O andcrystallized from MeOH-Et₂O to yield (±)-6HCl (1.7 g, 63%): m.p. (HClsalt) >250° C.; ¹H NMR (HCl salt, DMSO-d6) δ1.8-2.0 (br s, 4H,—CH₂CH₂—), 2.2-3.9 (complex, 9H, 4 —CH₂— and 1 —CH—), 2.79 (s, 3H,—NCH₃), 3.48 (s, 3H, —OCH₃), 5.66 (s, 1H, —CH—), 6.1 (d, J=9.4 Hz, 1H,—CH—), 6.23 (s, 1H, aromatic), 6.77 (d of d, J=2.4 Hz and 8.4 Hz, 1H,aromatic), 7.09 (d, J=8.5 Hz, 1H, aromatic), 7.2-7.5 (complex, 10H,aromatic). MS (FAB) m/z 455. Anal. (C, H, N) C₃₀H₃₄N₂O₂.HCl.

EXAMPLE 352,2-Diphenyl-N-methyl-N-[(±)-trans-2-(1-pyrrolidinyl)-7-hydroxy-1,2,3,4-tetrahydronaphth-1-yl]acetamide((±)-7, ADL-01-0021-4)

With stirring in dry ice-acetone under N₂, 1.0 M BBr₃ in CH₂Cl₂ (19.7mL) was added at a fast drop rate to a solution of (±)-6 (1.491 g, 3.28mmol) in CH₂Cl₂ (20 mL), and the mixture was allowed to slowly warm to25° C. under N₂ as the dry ice sublimed. After 6.5 h, the mixture wasquenched with MeOH with ice-H₂O cooling and diluted with CH₂Cl₂ (50 mL).The mixture was partitioned between sat'd NaHCO₃ and CH₂Cl₂. Someyellowish precipitate was extracted into CH₂Cl₂ by adding some MeOH. Theorganic fraction was dried (Na₂SO₄), filtered through celite, andevaporated. The product was flash colum chromatographed eluting withCHCl₃:2% NH₃:2% MeOH to yield (±)-7 (0.426 g, 300%). Part of the freebase was converted to the HCl salt with 1.0 M HCl in Et₂O: ¹H NMR (freebase, CDCl₃) δ1.5-1.8 (br s, 4H, —CH₂CH₂—), 1.8-2.9 (complex, 9H, 4—CH₂— and 1 —CH—), 2.55 (s, 3H, —NCH₃), 5.21 (s, 1H, —CH—), 5.83 (d,J=8.6 Hz, 1H, —CH—), 6.22 (s, 1H, aromatic), 6.46 (m, 1H, aromatic),6.78 (d, J=8.1 Hz, 1H, aromatic), 7-7.4 (complex, 10H, aromatic). MS(FAB) m/z 441. Anal. (C, H, N) C₂₉H₃₂N₂O₂.HCl.H₂O.

EXAMPLE 362-(2-Nitro-4,5-dichlorophenyl-N-methyl-N-[(±)-trans-2-(1-pyrrolidinyl)-7-nitro-1,2,3,4-tetrahydronaphth-1-yl]acetamide((±)-8, ADL-01-0029-7)

ADL-01-0029-7 was prepared via the general DCC/pyr coupling method from(±)-2 (0.5790 g, 2.103 mmol), 2-nitro-4,5-dichlorophenylacetic acid(1.0512 g, 4.204 mmol), DCC (0.8948 g, 4.34 mmol), and pyr (0.35 mL, 4.3mmol). After stirring at 25° C. overnight, more2-nitro-4,5-dichlorophenylacetic acid (1.0510 g, 4.203 mmol), DCC(0.8946 g, 4.34 mmol), and CH₂Cl₂ (10 mL) were added, and after 5 h, thereaction was worked up according to the general procedure. The crudeproduct was purified by gravity column eluting with CH₂Cl₂:2% NH₃ beforeit was converted to the HCl salt with 1.0 M HCl in Et₂O and washed withhot MeOH to yield (±)-8.HCl (0.4948 g, 43% yield): m.p. (HCl salt) >250°C.; ¹H NMR (HCl salt, DMSO-d₆) δ1.8-2. (br s, 4H, —CH₂CH₂—), 2.2-4.6(complex, 11H, 5 —CH₂— and 1 —CH—), 2.9 (s, 3H, —NCH₃), 6.1 (d, J=10.2Hz, 1H, —CH—), 7.53 (d, J=8.5 Hz, 1H, aromatic), 7.89 (s, 1H, aromatic),7.91 (s, 1H, aromatic), 8.12 (d of d, J=2.2 Hz and 8.5 Hz, 1H,aromatic), 8.4 (s, 1H, aromatic). MS (FAB) m/z 507. Anal. (C, H, N)C₂₃H₂₄N₄O₅Cl₂.HCl.

EXAMPLE 372-(3,4-Dichlorophenyl)-N-methyl-N-[(±)-trans-2-(1-pyrrolidinyl)-7-nitro-1,2,3,4-tetrahydronaphth-1-yl]acetamide((±)-9, ADL-01-0031-3)

ADL-01-0031-3 was prepared via the general DCC/pyr coupling procedurefrom (±)-2 (1.8173 g, 6.600 mmol), 3,4-dichlorophenylacetic acid (2.7066g, 13.20 mmol), DCC (2.8057 g, 13.60 mmol), and pyr (1.10 mL, 13.6mmol). The product was purified by flash column eluting with CH₂Cl₂:2%NH₃:1% MeOH before it was converted to the HCl salt with Et₂O—HCl andwashed with hot MeOH to yield (±)-9.HCl (2.49 g, 76%): m.p. (HCl salt)255-257° C.; ¹H NMR (HCl salt, DMSO-d₆) δ1.8-2 (br s, 4H, —CH₂CH₂—),2-4.2 (complex, 11H, 5 —CH₂— and 1 —CH—), 2.83 (s, 3H, —NCH₃), 6.1 (d,J=9.8 Hz, 1H, —CH—), 7.3-7.7 (complex, 5H, aromatic), 8.06 (d of d,J=2.4 Hz and 8.6 Hz, 1H, aromatic). MS (FAB) m/z 462. Anal. (C, H, N)C₂₃H₂₅N₃O₃Cl₂.HCl.

EXAMPLE 382-(3,4-Dichlorophenyl)-N-methyl-N-[(±)-trans-2-(1-pyrrolidinyl)-7-amino-1,2,3,4-tetrahydronaphth-1-yl]acetamide((±)-10, ADL-01-0032-1)

With stirring at 55° C., Raney nickel (50% slurry in H₂O) was added insmall portions to a mixture of (±)-9 (2.10 g, 4.54 mmol) and hydrazinehydrate (4 mL) in EtOH (60 mL) until all hydrazine was decomposed in 30min. The mixture was filtered through celite, and the Raney nickel waswashed with hot MeOH (120 mL). The filtrate was evaporated and dried invacuo before the residue was partitioned between sat'd NaHCO₃ andCH₂Cl₂, which was dried (Na₂SO₄), filtered through celite, andevaporated. The product was purified by gravity column eluting withCHCl₃:2% NH₃:0.5% MeOH before it was converted to the HCl salt withEt₂O—HCl to yield (±)-1.0.HCl (0.3 g, 14%, unoptimized): m.p. (HClsalt) >250° C.; ¹H NMR (free base, CDCl₃) δ1.64 (br s, 4H, —CH₂CH₂—),1.9-3.8 (complex, 11H, 5 —CH₂— and 1 —CH—), 2.59 (s, 3H, —NCH₃), 5.8 (d,J=9.7 Hz, 1H, —CH—), 6.29 (s, 1H, aromatic), 6.43 (d, J=8 Hz, 1H,aromatic), 6.8 (d, J=8 Hz, 1H, aromatic), 7.17 (d, J=8 Hz, 1H,aromatic), 7.3 (m, 2H, aromatic). MS (FAB) m/z 432. Anal. (C, H, N)C₂₃H₂₇N₃OCl₂2HCl.

EXAMPLE 392-(4-Methylsulfonylphenyl)-N-methyl-N-[(±)-trans-2-(1-pyrrolidinyl)-7-nitro-1,2,3,4-tetrahydronaphth-1-yl]acetamide((±)-11, ADL-01-0034-7)

ADL-01-0034-7 was prepared via the general DCC/pyr coupling procedurefrom (±)-2 (0.3414 g, 1.240 mmol), 4-methylsulfonylphenylacetic acid(0.5309 g, 2.478 mmol), DCC (0.5288 g, 2.563 mmol), and pyr (0.21 mL,2.55 mmol). After stirring at 25° C. overnight, more of4-methylsulfonylphenylacetic acid (0.5307 g, 2.477 mmol), DCC (1.1356 g,5.504 mmol), and CH₂Cl₂ (13 mL) were added, and the mixture was workedup according to the general procedure after another night of stirring.The product was purified by gravity column eluting with CHCl₃:2% NH₃:1%MeOH before it was converted to the HCl salt with Et₂O—HCl and washedwith hot MeOH to yield (±)-11.HCl (0.4455 g, 76%): m.p. (HCl salt)284-285° C.; ¹H NMR (HCl salt, DMSO-d₆) δ1.96 (br s, 4H, —CH₂CH₂—),2.1-4.3 (complex, 11H, 5 —CH₂— and 1 —CH—), 2.88 (s, 3H, —NCH₃), 3.24(s, 3H, —SO₂CH₃), 6.13 (d, J=10 Hz, 1H, —CH—), 7.51 (d, J=8.8 Hz, 1H,aromatic), 7.68 (m, 3H, aromatic), 7.9 (d, J=8.7 Hz, 2H, aromatic), 8.08(d of d, J=2.6 Hz and 8.5 Hz, 1H, aromatic). MS (FAB) m/z 472. Anal. (C,H, N) C₂₄H₂₉N₃O₅S.HCl.0.25CH₂Cl₂.

EXAMPLE 402-(3,4-Dichlorophenyl)-N-methyl-N-{[±]-trans-2-[1-pyrrolidinyl]-7-[N,N-bis(t-butoxycarbonylmethyl)-amino]-1,2,3,4-tetrahydronaphth-1-yl}acetamide((±)-12, ADL-01-0037-0)

With stirring in ice-H₂O under N₂, t-butyl bromoacetate (0.34 mL, 2.32mmol) was added dropwise to a mixture of (±)-10 (0.4014 g, 0.928 mmol)and NEt(iPr)₂ (0.81 mL, 4.64 mmol) in dry THF (10 mL). After 10 min, themixture was stirred at 25° C. under N₂ overnight before more t-butylbromoacetate (0.30 mL) was added at 25° C. After stirring overnight,more NEt(iPr)₂ (0.40 mL) and t-butyl bromoacetate (0.30 mL) were added,and after one more night of stirring, the mixture was partitionedbetween sat'd NaHCO₃ and CH₂Cl₂. The aqueous fraction was extracted withmore CH₂Cl₂, and the combined organic fraction was dried (Na₂SO₄),filtered through celite, and evaporated. The crude product was purifiedby gravity column eluting with CH₂Cl₂:2% NH₃:1% MeOH before part of thefree base was converted to the HCl salt with 1.0 M HCl in Et₂O withstirring in ice-H₂O. The residue was sonicated in hexane to yield(±)-12.2HCl (0.1610 g, 25%, unoptimized): m.p. (HCl salt) 143° C. (dec);¹H NMR (free base, CDCl₃) δ1.39 (s, 9H, t-butyl), 1.43 (s, 9H, t-butyl),1.65 (br s, 4H, —CH₂CH₂—), 1.9-4.1 (complex, 15H, 7 —CH₂— and 1 —CH—),2.58 (s, 3H, —NCH₃), 5.8 (m, 1H, —CH—), 6.2-7.4 (complex, 6H, aromatic).MS (FAB) 660. Anal. (C, H, N) C₃₅H₄₇N₃O₅Cl₂.2HCl.0.5CH₃CN.

EXAMPLE 412-(3,4-Dichlorophenyl)-N-methyl-N-{[±]-trans-2-[1-pyrrolidinyl]-7-[N,N-bis-(carboxymethyl)amino]-1,2,3,4-tetrahydronaphth-1-yl}acetamide((±)-13, ADL-01-0044-6)

A solution of (±)-12 (0.35 g, 0.5 mmol) in 1:1 AcOH and 3 N HCl (8 mL)with some anisole (2 drops) was stirred at 2.5° C. overnight beforeconc. HCl (0.5 mL) was added, and the mixture was warmed to 40° C. for 1h. Then some anisole (4 drops) was added, and the mixture was stirred at25° C. for 5 h before it was evaporated. The residue was sequentiallyevaporated from iPrOH and PhCH₃ before it was sonicated with Et₂O toyield (±)-13.HCl (0.2360 g, 81%): m.p. (HCl salt) 160° C. (dec); ¹H NMR(HCl salt, DMSO-d₆) δ1.93 (br s, 4H, —CH₂CH₂—), 2.2-4.3 (complex, 15H, 7—CH₂— and 1 —CH—), 2.79 (s, 3H, —NCH₃—), 5.93 (d, J=10.7 Hz, 1H, —CH—),6.37 (s, 1H, aromatic), 6.68 (d, J=8.8 Hz, 1H, aromatic), 7.00 (d, J=8.1Hz, 1H, aromatic), 7.40 (d, J=8.1 Hz, 1H, aromatic), 7.63 (m, 2H,aromatic). MS (FAB) m/z 490 (M+1-CH₂CO₂H). Anal. (C, H, N)C₂₇H₃₁N₃O₅Cl₂.1HCl.

EXAMPLE 422-(3,4-Dichlorophenyl)-N-methyl-N-{[±]-trans-2-[1-pyrrolidinyl]-7-[N,N-bis-(ethoxycarbonylmethyl)-amino]-1,2,3,4-tetrahydronaphth-1-yl}acetamide((±)-14, ADL-01-0052-9)

With stirring in ice-H₂O under N₂, ethyl bromoacetate (0.47 mL, 4.21mmol) was added dropwise to a mixture of (±)-10 (0.3640 g, 0.842 mmol)and NEt(iPr)₂ (0.88 mL, 5.05 mmol) in dry THF (6 mL). After 10 min, themixture was stirred at 25° C. under N₂ overnight before it waspartitioned between sat'd NaHCO₃ and CH₂Cl₂. The aqueous fraction wasextracted with more CH₂Cl₂, and the combined organic fraction was dried(Na₂SO₄), filtered through celite, and evaporated. The product waspurified by gravity column eluting with CH₂Cl₂:2% NH₃:1% MeOH before itwas converted to the HCl salt with 1.0 M HCl in Et₂O and washed withEt₂O to yield (±)-14.HCl (0.27 g, 47%): m.p. (HCl salt) 128° C. (dec);¹H NMR (HCl salt, DMSO-d₆) δ1.2 (m, 6H, 2 —CH₃), 1.9 (br s, 4H,—CH₂CH₂—), 2.2-4.4 (complex, 19H, 9 —CH₂— and 1 —CH—), 2.78 (s, 3H,—NCH₃), 5.9 (d, J=10.3 Hz, 1H, —CH—), 6.14 (s, 1H, aromatic), 6.49 (d,J=8.2 Hz, 1H, aromatic), 6.91 (d, J=8.3 Hz, 1H, aromatic), 7.39 (d,J=8.3 Hz, 1H, aromatic), 7.6 (m, 2H, aromatic). MS (FAB) m/z 605. Anal.(C, H, N) C₃₁H₃₉N₃O₅Cl₂.1.25HCl.0.3CH₃CN.

EXAMPLE 432-(3,4-Dichlorophenyl)-N-methyl-N-[(±)-trans-2-(1-pyrrolidinyl)-7-(N-diethylphosphoramidato-amino)-1,2,3,4-tetrahydronaphth-1-yl]acetamide((±)-15 ADL-01-0053-7)

With stirring in ice-H₂O under N₂, diethyl chlorophosphate (0.57 mL,3.92 mmol) was added dropwise to a mixture of (±)-10 (0.3393 g, 0.785mmol) and NEt(iPr)₂ (0.82 mL, 4.71 mmol) in dry THF (6 mL). After 10min, the mixture was stirred at 25° C. under N₂ overnight before themixture was evaporated and dried in vacuo. The residue was partitionedbetween sat'd NaHCO₃ and CH₂Cl₂. The aqueous fraction was extracted withmore CH₂Cl₂, and the combined organic fraction was dried (Na₂SO₄),filtered through celite, and evaporated. The product was purified bygravity column eluting with CH₂Cl₂:2% NH₃:1.5% MeOH before it wasconverted to the HCl salt with 1.0 M HCl in Et₂O and sonicated in Et₂Oto yield (±)-15.HCl (0.4205 g, 89%): m.p. (HCl salt) 247-249° C.; ¹H NMR(HCl salt, DMSO-d₆) δ1.2 (m, 6H, 2 —CH₃), 1.95 (br s, 4H, —CH₂CH₂—),2.2-4.1 (complex, 15H, 7 —CH₂— and 1 —CH—), 2.75 (s, 3H, —NCH₃), 5.98(d, J=10.3 Hz, 1H, —CH—), 6.7 (s, 1H, aromatic), 6.9 (m, 1H, aromatic),7.03 (d, J=8.4 Hz, 1H, aromatic), 7.3 (d of d, J=2 Hz and 8.2 Hz, 1H,aromatic), 7.6 (m, 2H, aromatic), 7.9 (d, J=9.7 Hz, —NHP). MS (FAB) m/z568. Anal. (C, H, N) C₂₇H₃₆N₃O₄PCl₂.HCl.0.25H₂O.

EXAMPLE 442-(3,4-Dichlorophenyl)-N-methyl-N-{[±]-trans-2-[1-pyrrolidinyl]-7-[N-2-(diethylphosphoryl)ethyl-amino]-1,2,3,4-tetrahydronaphth-1-yl}acetamide((±)-16, ADL-01-0070-1)

With stirring in ice-H₂O under N₂, diethyl 2-bromoethylphosphonate(0.8601 g, 3.52 mmol) was added to a mixture of (±)-10 (0.3042 g, 0.704mmol) and NEt(iPr)₂ (0.74 mL, 4.2 mmol) in dry THF (4 mL). After 10 min,the mixture was stirred at 25° C. under N₂ for 2.5 days before morediethyl 2-bromoethylphosphonate (0.8546 g) and NEt(iPr)₂ (0.74 mL, 4.2mmol) were added. After stirring for 14 more days, the mixture wasevaporated to dryness and dried in vacuo before the residue waspartitioned between sat'd NaHCO₃ and CH₂Cl₂. The aqueous fraction wasextracted with more CH₂Cl₂, and the combined organic fraction was dried(Na₂SO₄), filtered through celite, and evaporated. The product waspurified by gravity column eluting with CH₂Cl₂:2% NH₃:1% MeOH and thenby radial chromatography eluting with CH₂Cl₂:2% NH₃. The product wasconverted to the HCl salt with 1.0 M HCl in Et₂O and solidified byevaporation from CH₂Cl₂ and sonication with Et₂O to yield (±)-16.HCl(0.2466 g, 52%): m.p. (HCl salt) 151° C. (dec); ¹H NMR (HCl salt,DMSO-d₆) δ1.24 (t, J=7 Hz, 6H, 2 —CH₃), 1.93 (br s, 4H, —CH₂CH₂—), 2-4.3(complex, 19H, 9 —CH₂— and 1 —CH—), 2.8 (s, 3H, —NCH₃), 5.96 (d, J=10.2Hz, 1H, —CH—), 6.69 (br s, 1H, aromatic), 6.87 (d, J=7.5 Hz, 1H,aromatic), 7.11 (d, J=8.1 Hz, 1H, aromatic), 7.43 (d, J=8.3 Hz, 1H,aromatic), 7.64 (m, 2H, aromatic). MS (FAB) m/z 596. Anal. (C, H, N)C₂₉H₄₀N₃O₄PCl₂.2HCl.

EXAMPLE 452-(3,4-Dichlorophenyl)-N-methyl-N-[(±)-trans-2-(1-pyrrolidinyl)-6-methoxy-7-(N-benzyl-N-methylaminosulfonyl)-1,2,3,4-tetrahydronaphth-1-yl]acetamide((±)-19, ADL-01-0090-9)

ADL-01-0090-9 was prepared via the general DCC/pyr coupling procedurefrom (±)-17 (0.6213 g, 1.40 mmol), 3,4-dichlorophenylacetic acid (0.5764g, 2.81 mmol), DCC (0.5951 g, 2.88 mmol), and pyr (0.23 mL, 2.88 mmol).The product was gravity column chromatographed eluting with CH₂Cl₂:2%NH₃:1% MeOH and further purified by radial chromatography eluting withCH₂Cl₂:2% NH3. The product was converted to the HCl salt with 1.0 M HClin Et₂O to yield (±)-19.HCl (0.3 g, 32%): m.p. (HCl salt) 150° C. (dec);¹H NMR (HCl salt, DMSO-d₆) δ1.91 (br s, 4H, —CH₂CH₂—), 2.2 4.1 (complex,11H, 5 —CH₂— and 1 —CH—), 2.55 (s, 3H, —NCH₃), 2.77 (s, 3H, —NCH₃), 3.88(s, 3H, —OCH₃), 4.2 (s, 2H, —CH₂Ph), 6.0 (d, J=9.7 Hz, 1H, —CH—), 7.10(s, 1H, aromatic), 7.2-7.4 (complex, 7H, aromatic), 7.55 (m, 2H,aromatic). MS (FAB) m/z 630. Anal. (C, H, N) C₃₂H₃₇N₃O₄Cl₂S.HCl.0.5H₂O.

EXAMPLE 462-(3,4-Dichlorophenyl)-N-methyl-N-[(±)-trans-2-(1-pyrrolidinyl)-7-(N-benzyl-N-methylaminosulfonyl)-1,2,3,4-tetrahydronaphth-1-yl]acetamide((±)-20, ADL-01-0099-0)

ADL-01-0099-0 was prepared via the general DCC/pyr coupling procedurefrom (±)-18 (0.4530 g, 1.095 mmol), 3,4-dichlorophenylacetic acid(0.4485 g, 2.19 mmol), DCC (0.4677 g, 2.27 mmol), and pyr (,0.18 mL,2.26 mmol). The product was purified by flash column eluting withCH₂Cl₂:2% NH3 and then by radial chromatography eluting with CH₂Cl₂:2%NH₃. The product was converted to the HCl salt with 1.0 M HCl in Et₂Oand then washed with hot MeOH to yield (±)-20.HCl (0.33 g, 47%): m.p.(HCl salt) 251-254° C.; ¹H NMR (HCl salt, DMSO-d₆) δ1.97 (br s, 4H,—CH₂CH₂—), 2.3-4.2 (complex, 13H, 6 —CH₂— and 1 —CH—), 2.49 (s, 3H,13NCH₃), 2.90 (s, 3H,13 NCH₃), 6.17 (d, J=10.4 Hz, 1H, —CH—), 7.2-7.8(complex, 11H, aromatic). MS (FAB) m/z 600. Anal. (C, H, N)C₃₁H₃₅N₃SO₃Cl₂.HCl.

EXAMPLE 47 2-(2-Nitro-4,5-dichlorophenyl)-N-methyl-N-[35)-trans-2-(1-pyrrolidinyl)-indan-1-yl]acetamide ((±)-24, ADL-01-0104-8)

ADL-01-0104-8 was prepared via the general DCC/pyr coupling procedurefrom (±)-23 (0.4265 g, 1.971 mmol), 2-nitro-4,5-dichlorophenylaceticacid (0.9859 g, 3.943 mmol), DCC (0.8350 g, 4.047 mmol), and pyr (0.33mL, 4.06 mmol). The crude product was purified by silica gel columneluting with CH₂Cl₂:2% NH₃ before it was converted to the HCl salt with1.0 M HCl in Et₂O and crystallized from MeOH to yield (±)-24.HCl (0.3630g, 38%, first crop): m.p. (HCl salt) 284-287° C. ¹H NMR (HCl salt,DMSO-d₆) δ1.8-2.1 (br s, 4H, —CH₂CH₂—), 2.84 (s, 3H, —NCH₃), 3-4.4(complex, 9H, 4 —CH₂— and 1 —CH—), 6.37 (d, J=8 Hz, 1H, —CH—), 7.08 (brs, 1H, aromatic), 7.3 (m, 3H, aromatic), 7.92 (s, 1H, aromatic), 8.41(s, 1H, aromatic). MS (FAB) m/z 448. Anal. (C, H, N) C₂₂H₂₃N₃O₃Cl₂.HCl.

EXAMPLE 482-(2-Nitro-4-trifluoromethylphenyl)-N-methyl-N-[(±)-trans-2-(1-pyrrolidinyl)-indan-1-yl]acetamide((±)-26, ADL-01-0106-3)

ADL-01-0106-3 was prepared via the general DCC/pyr coupling procedurefrom (±)-23 (0.3229 g, 1.492 mmol), 2-nitro4-trifluoromethylphenylaceticacid (0.5579 g, 2.24 mmol), DCC (0.5512 g, 2.67 mmol), and pyr (0.19 mL,2.31 mmol). The crude product was gravity column chromatographed elutingwith CH₂Cl₂:2% NH3 before it was converted to the HCl salt with 1.0 MHCl in Et₂O and crystallized from MeOH-Et₂O to yield (±)-26.HCl (0.3643g, 50%): m.p. (HCl salt) 249-250° C.; ¹H NMR (HCl salt, DMSO-d₆)δ1.8-2.1 (br s, 4H, —CH₂CH₂—), 2.89 (s, 3H, —NCH₃), 3-4.6 (complex, 9H,4 —CH₂— and 1 —CH—), 6.40 (d, J=8.1 Hz, 1H, —CH—), 7.1 (br s, 1H,aromatic), 7.3 (m, 3H, aromatic), 7.83 (d, J=8.1 Hz, 1H, aromatic), 8.17(d, J=7.8 Hz, 1H, aromatic), 8.41 (s, 1H, aromatic). MS (FAB) m/z 448.Anal. (C, H, N) C₂₃H₂₄N₃O₃F₃.HCl.

EXAMPLE 492,2-Diphenyl-N-methyl-N-[(±)-trans-2-(1-pyrrolidinyl)-indan-1-yl]acetamide((±)-28, ADL-01-0108-9)

ADL-01-108-9 was prepared via the general DCC/pyr coupling procedurefrom (±)-23 (0.2615 g, 1.209 mmol), diphenylacetic acid (0.5123 g, 2.41mmol), DCC (0.5138 g, 2.49 mmol), and pyr (0.20 mL, 2.5 mmol). The crudeproduct was purified by gravity column eluting with CH₂Cl₂:2% NH₃ beforeit was converted to the HCl salt with 1.0 M HCl in Et₂O and crystallizedfrom MeOH to yield (±)-28.HCl (0.3815 g, 71%): m.p. (HCl salt)>300° C.;¹H NMR (HCl salt, DMSO-d₆; the cis-trans rotamers are observed in about3.6 to 1 ratio. Only peaks for the major rotamer are reported.) δ1.88(br s, 4H, —CH₂CH₂—), 2.75 (s, 3H, —NCH₃), 3-4.2 (complex, 7H, 3 —CH₂—and 1 —CH—), 5.61 (s, 1H, —CH—), 6.5 (d, J=8 Hz, 1H, —CH—), 6.88 (d,J=6.5 Hz, 1H, aromatic), 7.1-7.4 (complex, 13H, aromatic). MS (FAB) m/z411. Anal. (C, H, N) C₂₈H₃₀N₂O.HCl.0.75 H₂O.

EXAMPLE 502-(4-Methylsulfonylphenyl)-N-methyl-N-[(±)-trans-2-(1-pyrrolidinyl)-indan-1-yl]acetamide((±)-29, ADL-01-0109-7)

ADL-01-0109-7 was prepared via the general DCC/pyr coupling procedurefrom (±)-23 (0.3271 g, 1.51 mmol), 4-methylsulfonylphenylacetic acid(0.6464 g, 3.017 mmol), DCC (0.6438, 3.12 mmol), and pyr (0.25 mL, 3.1mmol). The product was purified by gravity column eluting with CH₂Cl₂:2%NH₃ before it was converted to the HCl salt with 1.0 M HCl in Et₂O andcrystallized from MeOH-Et₂O to yield (±)-29.HCl (0.5295 g, 78%): m.p.(HCl salt) 246-248° C.; ¹H NMR (HCl salt, DMSO-d₆) δ1.8-2 (br s, 4H,—CH₂Cl₂—), 2.81 (s, 3H, —NCH₃), 2.9-4.2 (complex, 9H, 4 —CH₂— and 1—CH—), 3.21 (s, 3H, —SO₂CH₃), 6.4 (d, J=8.1 Hz, 1H, aromatic), 7 (m, 1H,aromatic), 7.3 (m, 3H, aromatic), 7.58 (d, J=8.1 Hz, 2H, aromatic), 7.9(d, J=7.3 Hz, 2H, aromatic). MS (FAB) m/z 413. Anal. (C, H, N)C₂₃H₂₈N₂SO₃.HCl.10.25H₂O.

The preparation of a compound of Formula IIA is shown in Example 2a.

EXAMPLE 2a(Z)-(±)-trans-[(7-Amino-2-(3,4-dichlorophenyl)-N-methyl-2-(1-pyrrolidinyl)-1,2,3,4-tetrahydronaphth-1-yl)acetamido]4-oxo-butenoicacid

To a solution of 7-amino compound (1)¹ (0.266 g, 0.614 mmol) inanhydrous THF (4.5 mL) under a nitrogen atmosphere was added a solutionof maleic anhydride (0.0602 g, 0.614 mmol) in anhydrous TH (0.53 mL).The reaction mixture was stirrred at room temperatature for 20 h and theresulting solid was filtered, washed with THF and ether, and dried invacuo. The solid was then suspended in hot waer, filtered, and dried togive 2, 0.267 g (82%); mp 221-223° C.; MS (FAB) 530 (M+1); ¹H NMR (200MHz, DMSO-d₆) δ1.50-1.93 (m, 2H), 2.00-3.10 (m, 9H), 2.66 (s, 3H), 3.83(m, 2H), 5.80 (m, 1H), 6.22 (m, 2H), 7.10 (d, J=7.5 Hz, 1H), 7.26 (s,1H), 7.35 (d, J=8.0 Hz, 1H), 7.48 (d, J=8.5 Hz, 1H), 7.55-7.65 (m, 2H).Anal. (C, H, N) C₂₇H₂₉N₃O₄Cl₂.0.5H₂O.

Ref.

1. U.S. Pat. No. 5,744,458

Compounds of Formula III

Compounds having the following structrues were prepared.

Compounds 1-5 were prepared by the method described in Chang, A.-C.Ph.D. Thesis, University of Minnesota-Twin Cities, 1995.

Compounds 9-19 were prepared from the appropriate arylacetic acids viaDCC/pyr coupling, followed by reduction, deprotection, and/orderivatization via known chemistry. Intermediate 8 was prepared via themethod described in Chang, A.-C. Ph.D. Thesis, University ofMinnesota-Twin Cities, 1995.

Intermediate 20 was prepared via minor modifications of knownmethods.^(7,8) Compounds 23 (EMD60400) and 24 (EMD61753) are knowncompounds that were synthesized in-house via minor modifications ofreported methods.⁹ Compounds 21, 22 and 25-27 were prepared by DCCcoupling, following by reduction where applicable.

Ref.

(7) Costello, G. F. et al. J. Med. Chem. 1991, 34, 181-189.

(8) Naylor, A. et al. J. Med. Chem. 1994, 37, 2138-2144.

(9) Gottschlich, R. et al. Bioorg. Med. Chem. Letters 1994, 4, 677-682.

EXAMPLE 51 2-(3,4-Dichlorophenyl)-N-methyl-N-{[1S]-1-[N-(S-asparticacid-a-amide-S-asparticacid-a-amido)-3-aminophenyl]-2-[1-pyrrolidinyl]ethyl}acetamide (6,ADL-01-0010-7)

With stirring in ice-H₂O under N₂, 1,3-dicyclohexylcarbodiimide (DCC,0.353 g, 1.711 mmol) and dry CH₂Cl₂ (2 mL) were added to a mixture of5-t-butyl ester (0.311 g, 0.538 mmol), N-Boc-L-aspartic acid-b-t-butylester (0.495 g, 1.711 mmol), and 1-hydroxybenzotriazole (HOBT, 0.232 g,1.717 mmol) in dry CH₂Cl₂ (8 mL). After 5 min, the mixture was stirredat 25° C. under N₂ overnight before H₂O (1 mL) was added, and themixture was filtered through celite. The 1,3-dicyclohexylurea (DCU) waswashed with CH₂Cl₂ (18 mL). The filtrate was partitioned between sat'dNaHCO₃ and CH₂Cl₂, which was dried (Na₂SO₄), filtered through celite,and evaporated. After flash column chromatography eluting with CH₂Cl₂:2%NH₃:2% MeOH, the protected intermediate (0.411 g, 90%) was dissolved in3N HCl (4 mL), AcOH (4 mL) with anisole (2 drops), and stirred at 25° C.overnight. The mixture was then evaporated to dryness, and evaporationfrom iPrOH then yielded ADL-01-0010-7: ¹H NMR (HCl salt, DMSO-d₆) δ2.0(br s, 4H, —CH₂CH₂—), 2.9 (s, 3H, NCH₃), 6.1 (br m, 1H, —CH—). MS (FAB)m/z 636. Anal. (C, H, N) C₂₉H₃₅N₅O₇Cl₂.1.5HCl.0.25iPrOH.

EXAMPLE 522-(3,4-Dichlorophenyl)-N-methyl-N-{[1S]-1-[N-(bis-methylsulfonamido)-3-aminophenyl]-2-[1-pyrrolidinyl]ethyl}acetamide(7, ADL-01-0011-5)

With stirring at 25° C., a solution of methanesulfonyl chloride (MsCl,0.25 mL, 3.2 mmol) in dry CH₂Cl₂ (0.75 mL) was added to a mixture ofADL-01-0007-3 (0.225 g, 0.554 mmol) and Et₃N (1 mL, 7 mmol) in dryCH₂Cl₂ (4 mL), and the mixture was stirred at 25° C. fitted with adrying tube. After 5 h, more CH₂Cl₂ (6 mL), MsCl (0.5 mL), and Et₃N (2mL) were added, and the mixture was stirred at 25° C. overnight beforeit was partitioned between CH₂Cl₂ (50 mL) and sat'd NaHCO₃. The aqueousfraction was extracted with more CH₂Cl₂ (25 mL), and the combinedorganic fraction was dried (Na₂SO₄), filtered through celite, andevaporated. Acetonitrile was used to azeotrope off Et₃N before theproduct was gravity column chromatographed twice eluting with CH₂Cl₂:2%NH₃:2% MeOH. The pure product was then treated with 1.0 M HCl in Et₂O toyield 7HCl (0.131 g, 39%, unoptimized): m.p. (HCl salt) 145° C. (dec);¹H NMR (free base, CDCl₃) δ1.7 (br s, 4H, —CH₂CH₂—), 2.4-3.8 (complex,8H, 4 —CH₂—), 2.7 (s, 3H, —NCH₃), 3.37 (s, 6H, 2 —SO₂CH₃), 6.1 (m, 1H,—CH—), 7.1-7.4 (complex, 7H, aromatic). MS (FAB) m/z 562. Anal. (C, H,N) C₂₃H₂₉N₃O₅S₂Cl₂.HCl.0.75H₂O.

EXAMPLE 532-(2-Nitrophenyl)-N-methyl-N-[(1S)-1-(3-nitrophenyl)-2-(1-pyrrolidinyl)ethyl]acetamide(10, ADL-01-0115-4)

ADL-01-0115-4 was prepared via the general DCC/pyr coupling procedurefrom 8 (1.4886 g, 5.97 mmol), 2-nitrophenylacetic acid (2.1619 g, 11.93mmol), DCC (2.5402 g, 12.31 mmol), and pyridine (1.00 mL, 12.36 mmol).The crude product was converted to the HCl salt with Et₂O—HCl withoutchromatography and crystallized from MeOH-Et₂O. The first crop wasrecrystallized again from MeOH-Et₂O to yield 10.HCl (1.3663 g, 51%):m.p. (HCl salt) 258-259° C.; ¹H NMR (HCl salt, DMSO-d₆) δ1.97 (br s, 4H,—CH₂CH₂—), 2.91 (s, 3H, —NCH₃), 3.11-4.45 (complex, 8H, 4 —CH₂—), 6.17(m, 1H, —CH—), 7.51-8.25 (complex, 8H, aromatic). MS (FAB) m/z 413.Anal. (C, H, N) C₂₁H₂₄N₄O₅.HCl0.25H₂O.

EXAMPLE 542-(2-Aminophenyl)-N-methyl-N-[(1S)-1-(3-aminophenyl)-2-(1-pyrrolidinyl)ethyl]acetamide(9, ADL-01-0113-9)

With stirring at 55° C., Raney nickel was added in small quantities to amixture of 10 (0.9857 g, 2.3899 mmol) and hydrazine hydrate (55%, 2 mL)in EtOH (30 mL) until gas evolution stopped in about 10 min. The mixturewas then filtered through celite, and the Raney nickel was washed withhot MeOH (100 mL). The filtrate was evaporated and dried in vacuo beforethe residue was partitioned between sat'd NaHCO₃ and CH₂Cl₂, which wasdried (Na₂SO₄), filtered through celite, and evaporated. The product wasgravity column chromatographed eluting with CHCl₃:2% NH₃:2% MeOH beforeit was converted to the HCl salt with Et₂O—HCl to yield 9.3HCl (0.3159g, 29%, unoptimized): m.p. (HCl salt) 219-222° C.; ¹H NMR (HCl salt,DMSO-d₆) δ1.98 (br s, 4H, —CH₂CH₂—), 2.87 (s, 3H, —NCH₃), 3.2-4.3(complex, 8H, 4 —CH₂—), 6.1 (m, 1H, —CH—), 7.11-7.45 (complex, 8H,aromatic). MS (FAB) m/z 353. Anal. (C, H, N) C₂₁H₂₈N₄O.3HCl.0.25H₂O.

EXAMPLE 55 2-(N-Diethylphosphoramidate-2-aminophenyl)-N-methyl-N-[(1S)-1-(N-diethylphosphoramidate-3-aminophenyl)-2-(1-pyrrolidinyl)ethyl]acetamide (11,ADL-01-0124-6)

With stirring in ice-H₂O under N₂, diethyl chlorophosphate (0.53 mL,3.67 mmol) was added to a mixture of 9 (0.2394 g, 0.6792 mmol) andNEt(iPr)₂ (0.77 mL, 4.40 mmol) in dry THF (5 mL). After 10 min, themixture was stirred at 25° C. under N₂ for 3.5 days before it wasdiluted with CH₂Cl₂, evaporated, and dried in vacuo. The residue waspartitioned between sat'd NaHCO₃ and CH₂Cl₂. The aqueous fraction wasextracted with more CH₂Cl₂, and the combined organic fraction was dried(Na₂SO₄), filtered through celite, and evaporated. The product waschromatographed eluting with CH₂Cl₂:2% NH₃:2% MeOH before it wasconverted to the HCl salt with 1.0 M HCl in Et₂O and crystallized fromiPrOH-Et₂O to yield 11.HCl (0.2364 g, 53%): m.p. (HCl salt) 184-186° C.;¹H NMR (HCl salt, DMSO-d₆) δ1.2 (m, 12H, 4 —CH₃), 1.96 (br s, 4H,—CH₂CH₂—), 2.81 (s, 3H, —NCH₃), 3-4 (complex, 16H, 8 —CH₂—), 6.05 (m,1H, —CH—), 6.7-7.3 (complex, 9H, aromatic and 1 NH), 8.08 (d, J=9.4 Hz,1H, NHP). MS (FAB) m/z 625. Anal. (C, H, N) C₂₉H₄₆N₄O₇P₂.HCl.

EXAMPLE 562-(N-Bis-sulfonamido-2-aminophenyl)-N-methyl-N-[(1S)-1-(N-bis-sulfonamido-3-aminophenyl)-2-(1-pyrrolidinyl)ethyl]acetamide(12, ADL-01-0126-1)

With stirring at 0° C. under N₂, MsCl (0.61 mL, 7.87 mmol) was added toa mixture of 9 (0.2774 g, 0.787 mmol) and Et₃N (2.2 mL, 15.7 mmol) inCH₂Cl₂ (8 mL). After 10-15 min, the mixture was stirred at 25° C. underN₂ overnight before the mixture was partitioned between sat'd NaHCO₃ andCH₂Cl₂. The aqueous fraction was extracted with more CH₂Cl₂, and thecombined organic fraction was dried (Na₂SO₄), filtered through celite,and evaporated. Acetonitrile was added to azeotrope off Et₃N. Theproduct was flash-column chromatographed eluting with CH₂Cl₂:2% NH₃before it was converted to the HCl salt with 1.0 M HCl in Et₂O to yield12.HCl (0.3564 g, 65%): m.p. (HCl salt) 180° C.; ¹H NMR (HCl salt,DMSO-d₆) δ2.0 (br s, 4H, —CH₂CH₂—), 2.76 (s, 3H, —NCH₃), 3-4.3 (complex,8H, 4 —CH₂—), 3.53 (s, 12 H, 4 —SO₂CH₃), 6.25 (m, 1H, —CH—), 7.3-7.6(complex, 8H, aromatic). MS (FAB) m/z 665. Anal. (C, H, N)C₂₅H₃₆N₄O₉S₄.HCl.MeOH.

EXAMPLE 572-(2-Nitro-4,5-dichlorophenyl)-N-methyl-N-[(1S)-1-(3-nitrophenyl)-2-(1-pyrrolidinyl)ethyl]acetamide(13, ADL-01-0128-7)

ADL-01-0128-7 was prepared via the general DCC/pyr coupling procedurefrom 8 (0.3690 g, 1.4801 mmol), 2-nitro-4,5-dichlorophenylacetic acid(0.7301 g, 2.920 mmol), DCC (0.6213 g, 3.01 mmol), and pyridine (0.24mL, 3.01 mmol). The crude product was converted to the HCl salt withEt₂O—HCl without chromatography and crystallized from MeOH to yield13.HCl (0.3232 g, 42%): m.p. (HCl salt) 165° C. (dec); ¹H NMR (HCl salt,DMSO-d₆) δ2.0 (br s, 4H, —CH₂CH₂—), 2.93 (s, 3H, —NCH₃), 3.1-4.3(complex, 6H, 3 —CH₂—), 4.4 (s, 2H, benzylic methylene), 6.2 (m, 1H,—CH—), 7.7-7.8 (m, 2H, aromatic), 7.9 (s, 1H, aromatic), 8.14 (s, 1H,aromatic), 8.27 (d, J=7.7 Hz, 1H, aromatic), 8.43 (s, 1H, aromatic). MS(FAB) m/z 481. Anal. (C, H, N) C₂₁H₂₂N₄O₅Cl₂.HCl.0.5MeOH.

EXAMPLE 582-(4-Methylsulfonylphenyl)-N-methyl-N-[(1S)-1-(3-nitrophenyl)-2-(1-pyrrolidinyl)ethyl]acetamide(14, ADL-01-0129-5)

ADL-01-0129-5 was prepared via the general DCC/pyr coupling procedurefrom 8 (0.5138 g, 2.061 mmol), 4-methylsulfonylphenylacetic acid (0.8825g, 4.119 mmol), DCC (0.8771 g, 4.251 mmol), and pyridine (0.34 mL, 4.245mmol). The crude product was gravity column chromatographed eluting withCHCl₃:2% NH₃ before it was converted to the HCl salt with 1.0 M HCl inEt₂O and crystallized from MeOH to yield 14.HCl (0.4695 g, 47%): m.p.(HCl salt) 276-277° C.; ¹H NMR (HCl salt, DMSO-d₆) δ2.0 (br s, 4H,—CH₂CH₂—), 2.92 (s, 3H, —NCH₃), 3.2 (s, 3H, —SO₂CH₃), 3.2-4.3 (complex,8H, 4 —CH₂—), 6.25 (m, 1H, —CH—), 7.61 (d, J=7.2 Hz, 2H, aromatic), 7.75(m, 2H, aromatic), 7.89 (d, J=7 Hz, 2H, aromatic), 8.12 (s, 1H,aromatic), 8.25 (m, 1H, aromatic). MS (FAB) m/z 446. Anal. (C, H, N)C₂₂H₂₇N₃O₅S.HCl.

EXAMPLE 592-(N-Butyloxycarbonyl-4-aminophenyl)-N-methyl-N-[(1S)-1-(3-nitrophenyl)-2-(1-pyrrolidinyl)ethyl]acetamide(18, ADL-01-0138-6)

ADL-01-0138-6 was prepared via the general DCC/pyr coupling method from8 (1.9948 g, 8.001 mmol), N-Boc-4-aminophenylacetic acid (3.0589 g,12.173 mmol), DCC (2.6602 g, 12.89 mmol), and pyridine (1.04 mL, 12.9mmol). The crude product was gravity column chromatographed eluting withCH₂Cl₂:2% NH₃:1% MeOH before it was converted to the HCl salt with 1.0 MHCl in Et₂O and crystallized from MeOH to yield 18.HCl (0.4891 g, 12%,first crop): m.p. (HCl salt) 170° C. (dec); ¹H NMR (HCl salt, DMSO-d₆)δ1.49 (s, 9H, t-butyl), 2.01 (br s, 4H, —CH₂CH₂—), 2.83 (s, 3H, —NCH₃),3.1-4.15 (complex, 8H, 4 —CH₂—) 6.27 (m, 1H, —CH—), 7.17 (d, J=8 Hz, 2H,aromatic), 7.39 (d, J=8 Hz, 2H, aromatic) 7.7 (m, 2H, aromatic), 8.09(s, 1H, aromatic), 8.23 (d, J=6 Hz, 1H, aromatic), 9.3 (s, 1H, —NHBoc).MS (FAB) 483. Anal. (C, H, N) C₂₆H₃₄N₄O₅.HCl.0.25H₂O.

EXAMPLE 602-(4-Aminophenyl)-N-methyl-N-[(1S)-1-(3-nitrophenyl)-2-(1-pyrrolidinyl)ethyl]acetamide(15, ADL-01-0132-9)

ADL-01-0138-6 (2.9211 g, 6.053 mmol) and anisole (2 drops) were mixed inAcOH (10 mL) and 4N HCl (10 mL) and stirred at 25° C. overnight, fittedwith a drying tube. The mixture was adjusted to pH 13 with 1N NaOH withstirring in ice-H₂O and then extracted with CH₂Cl₂ (2×70 mL). Thecombined organic fraction was dried (Na₂SO₄), filtered through celite,and evaporated. The product was gravity column chromatographed elutingwith CHCl₃:2% NH₃ before it was converted to the HCl salt with Et₂O—HClto yield 15.HCl (0.5531 g, 22%, unoptimized): m.p. (HCl salt) 200° C.(dec);¹H NMR (HCl salt, DMSO-d₆) δ1.98 (br s, 4H, —CH₂CH₂—), 2.86 (s,3H, —NCH₃), 3.2-4.3 (complex, 8H, 4 —CH₂—) 6.25 (m, 1H, —CH—), 7.16 (d,J=7.4 Hz, 2 H, aromatic), 7.33 (d, J=7.5 Hz, 2H, aromatic), 7.7 (m, 2H,aromatic), 8.08 (s, 1H, aromatic), 8.23 (m, 1H, aromatic). MS (FAB) m/z383. Anal. (C, H, N) C₂₁H₂₆N₄O₃.2HCl.0.75H₂O.

EXAMPLE 612-(N-Bis-sulfonamido-4-aminophenyl)-N-methyl-N-[(1S)-1-(3-nitrophenyl)-2-(1-pyrrolidinyl)ethyl]acetamide(16,ADL-01-0133-7)

With stirring in ice-H₂O under N₂, a solution of MsCl (1.56 mL, 20.17mmol) in CH₂Cl₂ (6 mL) was added dropwise over 2-3 min to a mixture of15 (1.5430 g, 4.0344 mmol) and Et₃N (5.6 mL, 40 mmol) in CH₂Cl₂ (24 mL).After 10 min, the mixture was stirred at 25° C. under N₂ overnightbefore the mixture was partitioned between CH₂Cl₂ and sat'd NaHCO₃. Theaqueous fraction was extracted with more CH₂Cl₂, and the combinedorganic fraction was dried (Na₂SO₄), filtered through celite, andevaporated. Acetonitrile was added to azeotrope off Et₃N before thecrude product was flash column chromatographed eluting with CH₂Cl₂:2%NH₃. The product was converted to the HCl salt with 1.0 M HCl in Et₂Oand washed with hot MeOH to yield 16.HCl (1.3091 g, 56%, first crop):m.p. (HCl salt) 257-259° C.; ¹H NMR (HCl salt, DMSO-d₆) δ1.99 (br s, 4H,—CH₂CH₂—), 2.87 (s, 3H, —NCH₃), 3.15-4.3 (complex, 8H, 4 —CH₂—), 3.51(s, 6H, 2 —SO₂CH₃), 6.25 (m, 1H, —CH—), 7.4 (m, 4H, aromatic), 7.7 (m,2H, aromatic), 8.1 (s, 1H, aromatic), 8.21 (m, 1H, aromatic). MS (FAB)m/z 539. Anal. (C, H, N) C₂₃H₃₀N₄O₇S₂.HCl.0.5CH₂Cl₂.

EXAMPLE 622-(N-Bis-sulfonamido-4-aminophenyl)-N-methyl-N-[(1S)-1-(3-aminophenyl)-2-(1-pyrrolidinyl)ethyl]acetamide(17, ADL-01-0136-0)

ADL-01-0136-0 was prepared from 16 (1.0729 g, 1.992 mmol), Raney nickel,and hydrazine hydrate (2 mL) in EtOH (30 mL). The conditions weresimilar to those used for the preparation of 9. The product was gravitycolumn chromatographed eluting with CH₂Cl₂:2% NH₃, and the purefractions were converted to the HCl salt with 1.0 M HCl in Et₂O to yield17.HCl (0.1194 g, 11%, unoptimized): m.p. (HCl salt) 252-255° C.; ¹H NMR(HCl salt, DMSO-d₆) δ2.0 (br s, 4H, —CH₂CH₂—), 2.86 (s, 3H, —NCH₃),3.1-4.2 (complex, 8H, 4 —CH₂—), 3.54 (s, 6H, 2 —SO₂CH₃), 6.1 (m, 1H,—CH—), 6.8-7.5 (complex, 8H, aromatic). MS (FAB) m/z 509. Anal. (C, H,N) C₂₃H₃₂N₄O₅S₂.1.75HCl.

EXAMPLE 632-(N-Bis-sulfonamido-4-aminophenyl)-N-methyl-N-[(1S)-1-(N-diethylphosphoramidate-3-aminophenyl)-2-(1-pyrrolidinyl)ethyl]acetamide (19,ADL-01-0139-4)

With stirring in ice-H₂O under N₂, diethyl chlorophosphate (0.84 mL,5.81 mmol) was added to a mixture of 17 (0.7383 g, 1.4514 mmol) andNEt(iPr)₂ (1.5 mL, 8.7 mmol) in dry THF (15 mL). After 10 min, themixture was stirred at 25° C. under N₂ overnight before more THF (15mL), NEt(iPr)₂ (0.76 mL), and diethyl chlorophosphate (0.42 mL) weresequentially added. After 3 h, the mixture was quenched with H₂O,diluted with CH₂Cl₂, evaporated, and dried in vacuo. The residue waspartitioned between CH₂Cl₂ and sat'd NaHCO₃. The aqueous fraction wasextracted with more CH₂Cl₂, and the combined organic fraction was dried(Na₂SO₄), filtered through celite, and evaporated. The crude product wasflash column chromatographed eluting with CH₂Cl₂:2% NH₃:1.5% MeOH beforeit was converted to the HCl salt with 1.0 M HCl in Et₂O and crystallizedfrom MeOH to yield 19.HCl (0.3274 g, 33%): m.p. (HCl salt) 245-247° C.;¹H NMR (HCl salt, DMSO-d₆) δ1.193 (t, J=7 Hz, 6H, 2 —CH₃), 1.95 (br s,4H, —CH₂CH₂—), 2.81 (s, 3H, —NCH₃), 3.1-4.1 (complex, 12H, 6 —CH₂—),3.52 (s, 6H, 2 —SO₂CH₃), 6.1 (m, 1H, —CH—), 6.79 (d, J=7.3 Hz, 1H,aromatic), 6.91 (s, 1H, aromatic), 6.99 (d, J=7.7 Hz, 1H, aromatic),7.23 (t, J=7.8 Hz, 1H, aromatic), 7.36 (d, J=8.3 Hz, 2H, aromatic), 7.44(d, J=8.6 Hz, 2H, aromatic), 8.09 (d, J=9.4 Hz, 1H, —NHP). MS (FAB) m/z645. Anal. (C, H, N) C₂₇H₄₁N₄O₈S₂P.HCl.

EXAMPLE 64

2-(2-Nitrophenyl)-N-methyl-N-{[1S]-phenyl-2-[1-(3S)-(3-hydroxypyrrolidinyl)]ethyl}acetamide(21, ADL-01-0055-2)

With stirring at 25° C. under N₂, DCC (0.160 g, 0.79 mmol) was added toa mixture of 2-nitrophenylacetic acid (0.140 g, 0.79 mmol) and pyridine(0.064 mL, 0.79 mmol) in CH₂Cl₂ (1.5 mL). After 3 min, a solution of 20(0.160 g, 0.72 mmol) in CH₂Cl₂ (1.5 mL) was added, followed by NEt(iPr)₂(0.375 mL, 2.15 mmol). The mixture was stirred at 25° C. under N₂overnight before sat'd NaHCO₃ was added, and the mixture was filteredthrough celite. The DCU was washed with a little CH₂Cl₂, and thefiltrate was partitioned between sat'd NaHCO₃ and CH₂Cl₂, which wasdried (MgSO₄), filtered through celite, and evaporated. Toluene wasadded to azeotrope off pyridine. The product was flash columnchromatographed eluting with CHCl₃:2% NH₃:2% MeOH before it wasconverted to the HCl salt with 1.0 M HCl in Et₂O and crystallized fromMeOH to yield 21.HCl (0.14 g, 47%): m.p. (HCl salt) 226-227° C.; ¹H NMR(HCl salt, DMSO-d₆) δ1.8-2.4 (m, 2H, —CH₂), 2.86 (s, 3H, —NCH₃), 3-4.5(complex, 8H, 4 —CH₂—), 5.5 (m, 1H, —CHOH), 6.1 (m, 1H, —CH—), 73-7.8(complex, 8H, aromatic), 8.11 (d, J=8 Hz, 1H, aromatic). MS (FAB) m/z384. Anal. (C, H, N) C₂₁H₂₅N₃O₄.HCl.0.5H₂O.

EXAMPLE 652-(2-Nitro-4,5-dichlorophenyl)-N-methyl-N-{[1S]-1-phenyl-2-[1-(3S)-(3-hydroxypyrrolidinyl)]ethyl}acetamide(22, ADL-01-0056-0)

ADL-01-0056-0 was prepared from 20 (0.2 g, 0.91 mmol),2-nitro-4,5-dichlorophenylacetic acid (0.45 g, 1.8 mmol), DCC (0.37 g,1.8 mmol), NEt(iPr)₂ (0.48 mL, 2.7 mmol), and pyridine (0.15 mL, 1.8mmol). The conditions are similar to those for the preparation of 21.The product was column chromatographed eluting with CH₂Cl₂:2% NH₃:1%MeOH before it was converted to the HCl salt with 1.0 M HCl in Et₂O andcrystallized from iPrOH to yield 22.HCl (0.060 g, 14%): m.p. (HCl salt)231-233° C. (dec); ¹H NMR (HCl salt, DMSO-d₆) δ1.8-2.4 (m, 2H, —CH₂—),2.85 (s, 3H, —NCH₃), 3.1-4.5 (complex, 8H, 4 —CH₂—), 5.5 (m, 1H, —CHOH),6.1 (m, 1H, —CH—), 7.2-7.5 (m, 5H, aromatic), 7.88 (s, 1H, aromatic),8.42 (s, 1H, aromatic). MS (FAB) m/z 452. Anal. (C, H, N)C₂₁H₂₃N₃O₄Cl₂.HCl.

EXAMPLE 662-(4-Methylsulfonylphenyl)-N-methyl-N-{[1S]-1-phenyl-2-[1-(3S)-(3-hydroxypyrrolidinyl)]ethyl}acetamide(25, ADL-01-0064-4)

ADL-01-0064-4 was prepared from 20 (0.2 g, 0.91 mmol),4-methylsulfonylphenylacetic acid (0.41 g, 1.8 mmol), DCC (0.37 g, 1.8mmol), pyridine (0.15 mL, 1.8 mmol), and NEt(iPr)₂ (0.48 mL, 2.7 mmol).The conditions are similar to those for the preparation of 21. Afterstirring at 25° C. overnight, more pyridine (0.075 mL, 0.9 mmol) and DCC(0.18 g, 0.9 mmol) were added, and the reaction was worked up the nextday. The product was purified by radial chromatography eluting withCH₂Cl₂:2% NH₃:1% MeOH before it was converted to the HCl salt with 1.0 MHCl in Et₂O and washed with hot iPrOH to yield 25.HCl (0.15 g, 36%):m.p. (HCl salt) 240-241° C.; ¹H NMR (HCl salt, DMSO-d₆) δ1.8-2.4 (m, 2H,—CH₂—), 2.8 (d, 3H, —NCH₃ of cis and trans amide rotamers), 3.23 (s, 3H,—SO₂CH₃), 3.1-4.5 (m, 8H, 4 —CH₂—), 5.5 (m, 1H, —CHOH), 6.15 (m, 1H,—CH—), 7.2-7.5 (m, 5H, aromatic), 7.55 (m, 2H, aromatic), 7.85 (m, 2H,aromatic). MS (FAB) m/z 417. Anal. (C, H, N) C₂₂H₂₈N₂O₄S.HCl.

EXAMPLE 672-(2-Nitro-4-trifluoromethylphenyl)-N-methyl-N-{[1S]-1-phenyl-2-[1-(3S)-(3-hydroxypyrrolidinyl]ethyl}acetamide(26, ADL-01-0067-7)

With stirring at 25° C. under N₂, DCC (0.39 g, 1.9 mmol) was added to amixture of 2-nitro-4-trifluoromethylphenylacetic acid (0.47 g, 1.9 mmol)and pyridine (0.15 mL, 1.9 mmol) in CH₂Cl₂ (10 mL). After 5 min, asolution of 20 (0.4 g, 1.8 mmol) in CH₂Cl₂ (5 mL) was added. After 2 h,more DCC (0.1 g, 0.5 mmol) was added, and the mixture was stirred at 25°C. overnight before more 2-nitro-4-trifluoromethylphenylacetic acid(0.045 g, 0.18 mmol) and DCC (0.1 g, 0.5 mmol) were added. After 2 h,the reaction was worked up as in the preparation of 21. The product waspurified by radial chromatography eluting with CH₂Cl₂:2% NH₃ before itwas converted to the HCl salt with 1.0 M HCl in Et₂O and precipitatedfrom CH₂Cl₂ to yield 26.HCl (0.050 g, 5.4%): ¹H NMR (HCl salt, DMSO-d₆)δ1.8-2.4 (m, 2H, —CH₂—), 2.87 (s, 3H, —NCH₃), 3.1-4.5 (complex, 8H, 4—CH₂—), 5.5 (m, 1H, —CHOH), 6.1 (m, 1H, —CH—), 7.2-7.5 (m, 5H,aromatic), 7.82 (d, J=7.7 Hz, 1H, aromatic), 8.16 (d, J=8 Hz, 1H,aromatic), 8.42 (s, 1H, aromatic). MS (FAB) m/z 452. Anal. (C, H, N)C₂₂H₂₄F₃N₃O₄.HCl.0.5H₂O.

EXAMPLE 682-(2-Amino-4-trifluoromethylphenyl)-N-methyl-N-{[1S]-1-phenyl-2-[1-(3S)-(3-hydroxypyrrolidinyl)]ethyl}acetamide(27, ADL-01-0076-8)

ADL-01-0076-8 was prepared from 26 (0.14 g, 0.31 mmol), Raney nickel,and hydrazine hydrate (0.2 mL) in EtOH (14 mL). The conditions weresimilar to those used for the preparation of 9. The product was purifiedby radial chromatography eluting with CHCl₃:2% NH₃:2% MeOH before it wasconverted to the HCl salt with Et₂O—HCl to yield 27.HCl (0.11 g, 77%):¹H NMR (DMSO-d₆) δ1.8-2.2 (m, 2H, —CH₂—), 2.88 (s, 3H, —NCH₃), 3.1-4.5(complex, 9H, 4 —CH₂— and 1 —CHOH), 6.2 (m, 1H, —CH—), 6.8-7.5 (complex,8 H, aromatic). MS (FAB) m/z 423. Anal (C, H, N)C₂₂H₂₆N₃O₂F₃.HCl.2.5H₂O.

Compounds of Examples 69-91 were prepared from the appropriatearylacetic acids/acid chlorides via EDCI/DIPEA or DCC/pyridinecouplings, followed by reduction, deprotection, and/or derivatizationvia known chemistry. Intermediate A was prepared via the method reportedin J. Med. Chem., 34, 1991 pp. 181-189, Costello, G. F. et al.

General Procedure for EDCI/DIPEA Coupling

To a solution of acid(1.1 eq.) and 1-Hydroxybenzotriazolehydrate(HOBT;1.1 eq.) in dry CH₂Cl in an ice-bath under N₂ was added1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI;1.1eq.). The mixture was stirred for 30 minutes. A solution of theamine(1.0 eq.) in dry methlylene chloride was added drop-wise followedby N,N-Diisopropylethyamine (DIPEA;1.5 eq.). The solution was allowed tostir at room temperature overnight. The reaction was quenched with sat.sodium bicarbonate and separated from methylene chloride. The organiclayer was dried (Na₂SO₄), filtered through Celite, and evaporated. Thecrude product was chromatographed and converted to the HCl salt.

EXAMPLE 692,2-Diphenyl-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide;ADL-01-0023-0

To a solution of Diphenylacetic acid(1.5 g;7.3 mmol) and pyridine(1.0mL;12.2 mmol) in 20 mL of dry methylene chloride at 25 degrees under N₂was added 1,3 dicyclohexylcarbodiimide, DCC(2.0 g;9.8 mmol). After 5minutes, 28(1.0 g;4.9 mmol) in 20 mL of dry methlylene chloride wasadded and the mixture was stirred overnight. TLC(95:5 methylenechloride:methanol with 2% ammonia) indicated all of the startingmaterial was consumed. The reaction was quenched with sat. sodiumbicarbonate and filtered through a Celite plug. The plug was rinsed withmethylene chloride and the aqueous layer was extracted with methylenechloride. The combined organic layers were dried (Na₂SO₄), filtered andconcentrated in vacuo to give 2.2 g of a light brown solid. The crudeproduct was purified by flash chromatography using a stepwise gradientof 2% to 8% MeOH:methylene chloride with 2% ammonia to afford 1.7 g(88%)of pure product which was treated with 1.0M HCl in diethyl ether to give29 as the HCl salt. ¹H NMR (HCl salt, DMSO-d₆) δ2.0(br s, 4H, —CH₂CH₂—),2.7(s,3H, —NCH₃), 6.2(br m,1H, —CH—), 7.1-7.5(complex, 15H, aromatic).MS (FAB) m/z 398. Anal.(C,H,N) C₂₇H₃₀N₂O.HCl.0.75H₂O.

EXAMPLE 70N′,N′-Diphenyl-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]urea;ADL01-0027-1

To a 0 degree solution of 28(500 mg;2.4 mmol) and triethylamine(731mL;5.2 mmol) in 10 mL of dry methylene chloride under N₂ was added asolution of Diphenylcarbamyl chloride(629 mg;2.7 mmol) in 5 mL of drymethylene chloride. The solution was warmed to room temperature andstirred overnight. TLC(95:5 methylene chloride: methanol with 2%ammonia) indicated the starting material was consumed. The reactionsolution was concentrated to a residue, which was pre-adsorbed ontosilica and purified using a stepwise gradient of 2% to 7% MeOH:methylenechloride with 2% ammonia to afford 350 mg(36%) of pure product which wastreated with 1.0M HCl in diethyl ether to give 30 as the HCl salt. ¹HNMR (HCl salt, DMSO-d₆) δ2.0 (br s, 4H, —CH₂CH₂—), 2.5(s, 3H,—NCH₃),5.8(br,m,1H,—CH—), 7.1-7.5(complex,15H, aromatic). MS(FAB) m/z 399.Anal.(C,H,N) C₂₆H₂₉N₃O.HCl.0.5H₂O.

EXAMPLE 712-(2-Nitrophenyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide;ADL-01-0030-5

ADL-01-0030-5 was prepared via the procedure described in thepreparation of 29 from 28(0.6 g;2.9 mmol), 2-nitrophenylacetic acid (0.8g;4.4 mmol), DCC(1.2g;5.8mmol), and pyridine(0.1 mL;1.4 mmol). The crudeproduct was purified by flash chromatography using a stepwise gradientof 2% to 7% MeOH:methylene chloride with 2% ammonia to afford 0.2 g(20%)of pure product which was treated with 1.0M HCl in diethyl ether to give31 as the HCl salt. ¹H NMR(HCl salt, DMSO-d₆) δ2.0(br s, 4H, —CH₂CH₂—),2.9(s, 3H,—NCH₃), 6.1(br,m, 1H, —CH—)7.3-8.1(complex, 9H, aromatic).MS(FAB) m/z 367. Anal. (C,H,N) C₂₁H₂₅N₃O₃.HCl.

EXAMPLE 722-(2-Nitro-4,5-dichlorophenyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide;ADL-01-0033-9

ADL-01-0033-9 was prepared via the general EDCI/DIPEA coupling procedurefrom 28 (1.4 g; 6.9 mmol), 2-nitro 4,5-dichlorophenylacetic acid (1.9 g;7.6 mmol), HOBT (1.0 g;7.6 mmol), EDCI(1.4 g;7.6 mmol), and pyridine(0.8mL;10.3 mmol). The crude product was purified by flash chromatographyusing a stepwise gradient of 2% to 5% MeOH: methylene chloride with 2%ammonia to afford 2.0 g(60%) of pure product which was treated with 1.0MHCl in diethyl ether to give 32 as the HCl salt. ¹H NMR(HCl salt,DMSO-d₆) δ2.0(br, s, 4H, —CH₂CH₂—), 2.9(s, 3H, —NCH₃), 6.1(br, m, 1H,—CH—), 7.2-7.6(complex, 5H, aromatic), 7.9(s, 1H, aromatic), 8.4(s, 1H,aromatic). MS(FAB) m/z 436. Anal. (C,H,N) C₂₁H₂₃N₃O₃Cl₂.HCl.0.25 H₂O.

EXAMPLE 732-(4-Methylsulfonylphenyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide;ADL-01-0036-2

ADL-01-0036-2 was prepared via the general EDCI/DIPEA coupling procedurefrom 28 (432 mg;2. mmol), 4-Methylsulfonylphenylacetic acid(500 mg;2.3mmol), HOBT (341 mg;2.5 mmol), EDCI(483 mg;2.5 mmol), and DIPEA(550mL;3.1 mmol). The crude product was purified by flash chromatographyusing a stepwise gradient of 2% to 4% MeOH:methylene chloride with 2%ammonia to afford 160 mg(19%) of pure product which was treated with1.0M HCl in diethyl ether to give 33 as the HCl salt. ¹H NMR(HCl salt,DMSO-d₆) δ2.0(br, s, 4H, —CH₂ CH₂—), 2.9(s, 3H, —NCH₃), 3.2(s, —SO₂CH₃),6.1(br, m, 1H, —CH—), 7.3-7.5(complex, 5H, aromatic), 7.6(br, d, 2H,aromatic), 7.9(br, d, 2H, aromatic). MS(FAB) m/z 400. Anal. (C,H,N)C₂₂H₂₈N₂O₃S.HCl.0.5 H₂O.

EXAMPLE 742-(2-Methoxyphenyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide;ADL-01-0049-5

ADL-01-0049-5 was prepared via the general EDCI/DIPEA coupling procedurefrom 28 (500 mg; 2.4 mmol), 2-Methoxyphenylacetic acid (610 mg; 3.6mmol), HOBT (495 mg; 3.6 mmol), EDCI (700 mg; 3.6 mmol), and DIPEA (850mL; 4.8 mmol). The crude product was purified by flash chromatographyusing a stepwise gradient of 1% to 7% MeOH:methylene chloride with 2%ammonia to afford 822 mg(96%) of pure product which was treated with1.0M HCl in diethyl ether to give 34 as the HCl salt. ¹H NMR (free base,CDCl₃) δ1.8(br, s, 4H, —CH₂CH₂—), 2.8(s, 3H, —NCH₃), 3.8(s, 3H, OCH₃),6.1(br, m, 1H, —CH—), 6.8-7.4(complex, 9H, aromatic). MS(FAB) m/z 352.Anal. (C,H,N) C₂₂H₂₈N₂O₂.HCl.

EXAMPLE 752-(3-Indolyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide;ADL-01-0054-5

ADL-01-0054-5 was prepared via the general EDCI/DIPEA coupling procedurefrom 28(500 mg;2.4 mmol), Indole-3-acetic acid(641 mg;3.6 mmol),HOBT(494 mg;3.6 mmol), EDCI(700 mg;3.6 mmol), and DIPEA(637 mL;3.6mmol). The crude product was purified by flash chromatography using astepwise gradient of 1% to 7% MeOH:methylene chloride to afford 761mg(88%) of pure product which was treated with 1.0M HCl in diethyl etherto give 35 as the HCl salt. ¹H NMR(HCl salt, CD₃OD) δ2.1(br, s, 4H,—CH₂CH₂—), 2.8(s, 3H, —NCH₃), 6.3(br, m, 1H, —CH—), 7.1-7.7(complex, 9H,aromatic). MS(FAB) m/z 361. Anal. (C,H,N) C₂₃H₂₇N₃O.HCl.1.0 H₂O.

EXAMPLE 762-(a,a,a-Trifluoro-p-tolyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide;ADL-01-0058-6

ADL-01-0058-6 was prepared via the general EDCI/DIPEA coupling procedurefrom 28(200 mg; 0.9 mmol), (a,a,a-Trifluoro-p-tolyl) acetic acid (239mg;1.1 mmol), HOBT(157 mg;1.1 mmol), EDCI(223 mg;1.1 mmol), andDIPEA(203 mL;1.1 mmol). The crude product was purified by flashchromatography using a stepwise gradient of 1% to 2% MeOH: methylenechloride to afford 354 mg(93%) of pure product which was treated with1.0M HCl in diethyl ether to give 36 as the HCl salt. ¹H NMR(HCl salt,CDCl₃) δ1.8(br, s, 4H, —CH₂CH₂—), 3.0(s, 3H, NCH₃), 6.4(br, m, 1H, CH),7.2-7.6(complex, 9H, aromatic). MS(FAB) m/z 390. Anal. (C,H,N)C₂₂H₂₅N₂OF₃.HCl.

EXAMPLE 772-(2-Nitro-a,a,a-Trifluro-4-tolyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide;ADL-01-0062-8

ADL-01-0062-8 was prepared via the general EDCI/DIPEA coupling procedurefrom 28(500 mg;2.4 mmol), (2-Nitro-a,a,a-trifluro-4-tolyl)aceticacid(728 mg;2.9 mmol), HOBT(395 mg;2.9 mmol),EDCI(559 mg;2.9 mmol), andDIPEA(510 mL;2.9 mmol). The crude product was purified by flashchromatography using a stepwise gradient of 2% to 10% MeOH:methylenechloride to afford 786 mg(74%) of pure product which was treated with1.0M HCl in diethyl ether to give 37 as the HCl salt. ¹H NMR(HCl salt,CDCl₃) d 2.0(br, s, 4H, —CH₂CH₂), 2.9(s, 3H, —NCH₃), 6.3(br, m, 1H, CH),7.1-7.5(complex, 4H, aromatic), 7.8-7.9(br, m, 2H, aromatic),8.3-8.4(br, s, 2H, aromatic). MS(FAB) m/z 435. Anal. (C,H,N)C₂₂H₂₄N₃O₃F₃.HCl.

EXAMPLE 78 2-(1-[4-Chlorobenzoyl)-5-methoxy-2-methylindole)-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide;ADL-01-0078-4

ADL-01-0078-4 was prepared via the general EDCI/DIPEA coupling procedurefrom 28(100 mg;0.4 mmol), (1-[p-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetic acid (189 mg;0.5 mmol),HOBT(73 mg;0.5 mmol), EDCI(101mg;0.5 mmol), and DIPEA (128 mL;0.7 mmol). The crude product waspurified by flash chromatography using a stepwise gradient of 2% to 5%MeOH:methylene chloride to afford 200 mg(79%) of pure product which wastreated with 1.0M HCl in diethyl ether to give 38 as the HCl salt. ¹HNMR(HCl salt, CDCl₃) δ1.6-1.8(br, m, 4H, —CH₂CH₂—), 2.3(b, s, 3H, —CH₃),2.9(br, s, —NCH₃), 3.8(br, s, 3H, —OCH₃), 6.7(br, m, 1H, —CH),7.1-7.6(complex, 12H, aromatic). MS(FAB) m/z 509. Anal. (C,H,N)C₃₂H₃₅N₃O₃Cl.HCl.

EXAMPLE 792-(4-Nitrophenyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide;ADL-01-0079-2

ADL-01-0079-2 was prepared via the general EDCI/DIPEA coupling procedurefrom 28(1.5 g;7.3 mmol), 4-Nitrophenylacetic acid(2.0 g;11.0 mmol),HOBT(1.4 g;11.0 mmol), EDCI(2.1 g;11.0 mmol), and DIPEA(2.5 mL;14.6mmol). The crude product was purified by flash chromatography using astepwise gradient of 1% to 5% MeOH:methylene chloride to afford 2.5g(93%) of pure product which was treated with 1.0M HCl in diethyl etherto give 39 as the HCl salt. ¹H NMR(HCl salt, CDCl₃) δ1.6(br, m, 4H,—CH₂CH₂—), 2.8(br, s, 3H, —NCH₃), 6.4(br, m,1H, —CH), 7.1-7.5(complex,7H, aromatic), 8.0(br, d, 2h, aromatic). MS (FAB) m/z 367. Anal. (C,H,N)C₂₁H₂₅N₃O₃.HCl.

EXAMPLE 802-(3-Nitrophenyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide;ADL-01-0084-2

ADL-01-0084-2 was prepared via the general EDCI/DIPEA coupling procedurefrom 28(1.5 g;7.3 mmol), 3-Nitrophenylacetic acid(2.0 g;11.0 mmol),HOBT(1.4 g;11.0 mmol), EDCI(2.1 g;11.0 mmol),and DIPEA(2.5 mL;14.6mmol). The crude product was purified by flash chromatography using astepwise gradient of 1% to 5% MeOH:methylene chloride with 2% ammonia toafford 2.6 g(100%) of pure product which was treated with 1.0M HCl indiethyl ether to give 40 is the HCl salt. ¹H NMR(HCl salt, CDCl₃)δ2.0(br, m, 4H, —CH₂CH₂—), 2.9(br, s, 3H, —NCH₃), 6.3(br, m, 1H, —CH),7.2-7.6(complex, 6H, aromatic), 7.8(br, d, 1H, aromatic),8.1-8.2(complex, 2H, aromatic). MS(AB) m/z 367. Anal. (C,H,N)C₂₁H₂₅N₃O₃.HCl.0.5H₂O.

EXAMPLE 812-(2-Pyridyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide;ADL-01-0085-9

ADL-01-0085-9 was prepared via the general EDCI/DIPEA coupling procedurefrom 28(350 mg;1.7 mmol),2-Pyridylacetic acid hydrochloride(326 mg;1.8mmol), HOBT (253 mg;1.8 mmol), EDCI(360 mg;1.8 mmol) and DIPEA(644mL;3.7 mmol). The crude product was purified by flash chromatographyusing a stepwise gradient of 2% to 5% MeOH:methylene chloride with 2%ammonia to afford 400 mg(72%) of pure product which was treated with 1.0m HCl in diethyl ether to give 41 as the HCl salt. ¹H NMR(free base,CDCl₃) δ1.7-1.9(br, m, 4H, —CH₂CH₂), 2.8(br, s, 3H, —NCH₃), 6.0-6.2(br,m, 1H, —CH), 7.1-7.8(complex, 8H, aromatic), 8.5(br, d, 1H, aromatic).MS(FAB) m/z 323. Anal. (C,H,N) C₂₀H₂₅N₃O.2HCl.0.5H₂O.

EXAMPLE 822-(3-Pyridyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide;ADL-01-0100-6

ADL-01-0100-6 was prepared via the general EDCI/DIPEA coupling procedurefrom 28 (120 mg;0.5 mmol), 3-Pyridylacetic acid hydrochloride (110mg;0.6 mmol), HOBT(85 mg;0.6 mmol), EDCI (120 mg;0.6 mmol), and DIPEA(280 mL;1.5 mmol). The crude product was purified by flashchromatography using a stepwise gradient of 1% to 6% MeOH:methylenechloride with 2% ammonia to afford 142 mg(76%) of pure product which wastreated with 1.0M HCl in diethyl ether to give 42 as the HCl salt. ¹HNMR(HCl salt, CDCl₃) δ2.1(br, m, 4H, —CH₂CH₂—), 2.9(br, s, 3H, —NCH₃),6.2-6.3(br, m, 1H, —CH), 7.2-7.3(complex, 5H, aromatic), 7.8-7.9(br, t,1H, aromatic), 8.6-8.9(complex, 3H, aromatic). MS(FAB) m/z 323. Anal.(C,H,N) C₂₀H₂₅N₃O.2HCl.1.25H₂O.

EXAMPLE 832-((+)-6-Methoxy-a-methyl-2-napthalene)-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide;ADL-01-0110-5

ADL-01-0110-5 was prepared via the general EDCI/DIPEA coupling procedurefrom 28(200 m;0.9 mmol), (+)-6-Methoxy-a-methyl-2-naphaleneaceticacid(217 mg;1.0 mmol), HOBT (142 mg;1.0 mmol), EDCI(201 mg;1.0 mmol),and DIPEA(256 mL;1.4 mmol). The crude product was purified by flashchromatography using a stepwise gradient of 1% to 2% MeOH:methylenechloride with 2% ammonia to afford 130 mg(33%) of pure product which wastreated with 1.0M HCl in diethyl ether to give 43 as the HCl salt. ¹HNMR(HCl salt, CDCl₃) δ1.4(d, 3H, —CH₃), 2.9(br, s, —NCH₃), 3.9(s,—OCH₃), 5.5(br, m, 1H, —CH), 7.0-7.7(complex, 11H, aromatic). MS(FAB)m/z 416. Anal. (C,H,N) C₂₇H₃₂N₂O₂.HCl.0.25H₂O.

EXAMPLE 842-(a,a,a-Trifluoro-3-tolyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide;ADL-01-0111-3

ADL-01-0111-3 was prepared via the general EDCI/DIPEA coupling procedurefrom 28 (200 mg;0.9 mmol), (a,a,a-Trifluoro-m-tolyl)acetic acid(214mg;1.0 mmol), HOBT (142 mg;1.0 mmol), EDCI(201 mg;1.0 mmol), andDIPEA(256 mL;1.4 mmol). The crude product was purified by flashchromatography using a stepwise gradient of 2% to 6% MeOH:methylenechloride to afford 250 mg(67%) of pure product which was treated with1.0M HCl in diethyl ether to give 44 as the HCl salt. 1H NMR(HCl salt,CDCl₃) δ2.0(br, m, 4H, —CH₂CH₂—), 2.9(br, s, 3H, —NCH₃), 6.4(br, m, 1H),7.1-7.7(complex, 9H, aromatic). MS (FAB) m/z 390. Anal. (C,H,N)C₂₂H₂₅N₂OF₃.HCl.

EXAMPLE 852-(4-Pyridyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide;ADL-01-0122-0

ADL-01-0122-0 was prepared via the general EDCI/DIPEA coupling procedurefrom 28 (120 mg;0.5 mmol),4-Pyridylacetic acid hydrochloride(150 mg;0.8mmol), HOBT (117 mg;0.8 mmol), EDCI(166 mg;0.8 mmol),and DIPEA(202mL;1.1 mmol). The crude product was purified by flash chromatographyusing a stepwise gradient of 2% to 5% MeOH:methylene chloride to afford172 mg(92%) of pure product which was treated with 1.0M HCl in diethylether to give 45 as the HCl salt. ¹H NMR(HCl salt, CDCl₃) δ2.1(br, m,4H, —CH₂CH₂—), 2.9(br, s, —NCH₃), 6.3(br, m, —CH), 7.2-7.3(complex, 5H,aromatic), 7.8(br, s, 2H, aromatic), 8.6(br, s, 2H, aromatic). MS (FAB)m/z 323. Anal. (C,H,N) C₂₀H₂₅N₃O.1.5HCl.0.5H₂O.

EXAMPLE 862-(a,a,a-Trifluoro-2-tolyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide;ADL-01-0123-8

ADL-01-0123-8 was prepared via the general EDCI/DIPEA coupling procedurefrom 28(200 mg;0.9 mmol),(a,a,a-Trifluoro-o-tolyl)acetic acid(239 mg;1.1mmol), HOBT(157 mg; 1.1 mmol), EDCI(223 mg;1.1 mmol), and DIPEA(203mL;1.1 mmol). The crude product was purified by flash chromatographyusing a stepwise gradient of 1% to 4% MeOH:methylene chloride with 2%ammonia to afford 339 mg(82%) of pure product which was treated with1.0M HCl in diethyl ether to give 46 as the HCl salt. ¹H NMR (HCl salt,CDCl₃) δ2.0(br, m, 4H—CH₂CH₂—), 2.9(br, s, —NCH₃), 6.3(br, m, 1H, —CH),7.1-7.7(complex, 9H, aromatic). MS (FAB) m/z 390. Anal. (C,H,N)C₂₂H₂₅N₂OF₃.HCl.

EXAMPLE 872-((S)-(+)-4-Isobutyl-a-methylphenyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide;ADL-01-0125-3

ADL-01-0125-3 was prepared via the general EDCI/DIPEA coupling procedurefrom 28(200 mg; 0.9 mmol),(S)-(+)-4-Isobutyl-a-methylphenylaceticacid(217 mg; 1.0 mmol), HOBT (142 mg; 1.0 mmol), EDCI(201 mg;1.0 mmol),and DIPEA(256 mL;1.4 mmol). The crude product was purified by flashchromatography using a stepwise gradient of 1% to 2% MeOH:methylenechloride with 2% ammonia to afford 240 mg(66%) of pure product which wastreated with 1.0M HCl in diethyl ether to give 47 as the HCl salt. ¹HNMR(HCl salt, CDCl₃) δ0.8(d, 6H, —(CH₃)₂), 1.4(d, 2H, —CH₃), 2.0(br, m,—CH₂CH₂—), 2.3-2.4(d, 2H, —CH₂—), 2.9(s, 3H, —NCH₃), 5.6(br, m, 1H,—CH), 7.0(br, q, 4H, aromatic), 7.3(br, s, 5H, aromatic). MS(FAB) m/z392. Anal. (C, H, N) C₂₆H₃₆N₂O.HCl.0.25H₂O.

EXAMPLE 882-(3,4,5-Trimethoxyphenyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide;ADL-01-0146-9

ADL-01-0146-9 was prepared via the general EDCI/DIPEA coupling procedurefrom 28(250 mg;1.2 mmol),3,4,5-Trimethoxyphenylacetic acid(304 mg;1.3mmol), HOBT(181 mg; 1.3 mmol), EDCI(256 mg;1.3 mmol), and DIPEA(318mL;1.8 mmol). The crude product was purified by flash chromatographyusing a stepwise gradient of 2% to 5% MeOH:methylene chloride with 2%ammonia to afford 500 mg(100%) of pure product which was treated with1.0M HCl in diethyl ether to give 48 as the HCl salt. ¹H NMR(free base,CDCl₃) δ1.7(br, m, 4H, —CH₂CH₂—), 2.7(s, 3H, —NCH₃), 3.8(d, 9H, —OCH₃),6.0-6.2(br, m, 1H, —CH), 6.4(s, 2H, aromatic), 7.1-7.3(complex, 5H,aromatic). MS (FAB) m/z 412. Anal. (C,H,N) C₂₄H₃₂N₂O₄.HCl.

EXAMPLE 892-(2-Aminophenyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamideADL-01-0024-8

Raney-Nickel(50% slurry in water) was added to a mixture of 31(2.30g;6.1 mmol), 2.2 mL(61.9 mmol) of hydrazine hydrate and 45 mL of abs.EtOH at 55 degrees to maintain a regular gas evolution. After 45 min.,TLC(95:5 methylene chloride:methanol w/2% ammonia) indicated that all ofthe starting material was consumed. The mixture was filtered through aCelite plug and rinsed with copious amounts of hot methanol. Thefiltrates were combined and concentrated in vacuo to afford 270 mg of awaxy solid. The crude product was purified by flash chromatography usinga stepwise gradient of 1% to 8% methanol:methylene chloride with 2%ammonia to afford 2.0 g(97%) of desired product. The pure product wastreated with 1.0M HCl in diethyl ether to yield 49(ADL-01-0024-8) as theHCl salt. ¹H NMR(HCl salt, DMSO-d₆) δ2.0(br, m, 4H, —CH₂CH₂—), 2.9(s,3H, —NCH₃), 6.1(br, m, 1H, —CH), 7.2(complex, 9H, aromatic). MS (FAB)m/z 321. Anal. (C,H,N) C₂₁H₂₇N₃O.2HCl.0.75H₂O.

EXAMPLE 902-(2-N,N-Dimethylsulfonamido-2-aminophenyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide;ADL-01-0060-2

To a solution of 49(400 mg;1.1 mmol) in 50 ml of dry methylene chloridewas added 429 mL of triethylamine and MsCl(913 mL; 11.8 mmol) dissolvedin 6 mL of dry methylene chloride. The dark red solution was allowed tostir overnight. TLC(95:5 methylene chloride:methanol w/2% ammonia)indicates the starting material is consumed. The reaction solution wasquenched with sat. sodium bicarbonate and the layers were separated. Theaqueous layer was extracted with methylene chloride and the combinedorganic layers were dried over anh. sodium sulfate, filtered and thesolvent was concentrated in vacuo to give 700 mg of a dark brownresidue. The crude product was purified by flash chromatography using astepwise gradient of 2% to 7% methanol:methylene chloride with 2%ammonia to afford 580 mg(97%) of desired product. The pure product wastreated with 1.0M HCl in diethyl ether to yield 50(ADL-01-0060-2) as theHCl salt. ¹H NMR(HCl salt, DMSO-d₆) δ2.0(br, m, 4H, —CH₂CH₂—), 2.7(br,s, 3H, —NCH₃), 3.5(br, s, (—SO₂CH₃)₂), 6.2(br, d, 1H, —CH),7.2-7.5(complex, 9H, aromatic). MS (FAB) m/z 493. Anal. (C,H,N)C₂₃H₃₁N₃O₅S₂.HCl.0.25H₂O.

EXAMPLE 912-(N-Methylsulfonamido-2-aminophenyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide;ADL-01-0075-0

To a solution of 50(500 mg;1.0 mmol) in 6 mL of 2:1 MeOH:THF was added4.0 mL of 1.0M NaOH. The solution was stirred for 20 min., after whichTLC(95:5 methylene chloride:methanol w/2% ammonia) indicates thereaction is complete. The reaction was quenched with 10% HCl and washedwith water and brine. The organic layer was dried over anil sodiumsulfate, filtered and concentrated in vacuo to give 381 mg of a brownsolid. The crude product was purified by flash chromatography using astepwise gradient of 2% to 4% methanol:methylene chloride with 2%ammonia to afford 326 mg(80%) of desired product. The pure product wastreated with 1.0M HCl in diethyl ether to yield 51(ADL-01-0075-0) as theHCl salt. ¹H NMR(HCl salt, CDCl₃) δ2.0(br, m, 4H, —CH₂CH₂—), 2.9(br, s,3H, —NCH₃), 3.0(s, 3H, —SO₂CH₃), 6.3(br, m, 1H, —CH), 7.0-7.2(complex,8H, aromatic), 7.5(br, d, 1H, aromatic). MS (FAB) m/z 415. Anal. (C,H,N)C₂₂H₂₉N₃O₃S.HCl.0.25H₂O.

EXAMPLE 922-(2-Amino4,5-dichlorophenyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide;ADL-01-0035-4

To a solution of 32(495 mg;1.0 mmol) in 25 mL of abs. EtOH was added 50mg of 10% Pd/C. The mixture was placed on a Parr apparatus under 10 psiof hydrogen. After 1 h, TLC(95:5 methylene chloride:methanol) indicatesno starting material remains. The mixture was filtered through a Celiteplug and basified with aq. ammonium hydroxide. The solvent wasconcentrated in vacuo to get a residue which was dissolved in EtOAc andwashed repeatedly with water. The organic layer was dried over anh.sodium sulfate, filtered and concentrated to give 200 mg of crude freebase. The crude product was treated with 1.0M HCl in diethyl ether anddried in a vacuum oven @ 80 degrees overnight to recover 120 mg(30%) of52(ADL-01-0035-4) as the HCl salt. ¹H NMR(HCl salt, CDCl₃) δ1.6-1.7(br,m, 4H, —CH₂CH₂—), 2.7(s, 3H, —NCH₃), 5.9-6.1(br, m, 1H, —CH),7.1-7.2(complex, 7H, aromatic). MS (FAB) m/z 406. Anal. (C,H,N)C₂₁H₂₅N₃OCl₂.HCl.1.5H₂O.

EXAMPLE 932-(N,N-Dimethysulfonamido-2-amino-4,5-dichlorophenyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide;ADL-01-0050-3

Same procedure as 50 using 223 mg(0.54 mmol) of 52, 0.5 mL(6.4 mmol) ofMsCl, 2.0 mL(14.3 mmol) of triethylamine and 25 mL of dry methylenechloride. The crude product was purified by flash chromatography using astepwise gradient of 1% to 3% MeOH:methylene chloride to yield 150mg(49%) of pure product which was treated with 1.0M HCl in diethyl etherto give 53(ADL-01-0050-3) as the HCl salt. ¹H NMR(HCl salt, CDCl₃)δ2.0(br, m, 4H, —CH₂CH₂—), 2.8(s, 3H, NCH₃), 3.3(d, 6H, —(SO₂CH₃)₂),6.2(br, m, 1H, —CH), 7.0-7.1(complex, 2H, aromatic), 7.3(complex, 5H,aromatic). MS (FAB) m/z 562. Anal. (C,H,N) C₂₃H₂₉N₃O₅S₂Cl₂.HCl.0.5H₂O.

EXAMPLE 942-(2-Amino,α,α,α-Trifluoro-4-toly)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide;ADL-01-0068-5

Same procedure as 49 using 710 mg(1.6 mmol) of 37, 0.5 mL(16.3 mmol) ofhydrazine hydrate in 50 mL of EtOH. The recovered product, 650 mg(98%crude recovery) was not purified any further. A small amount of thedesired product was treated with 1.0M HCl in diethyl ether to form54(ADL-01-0068-5) as the HCl salt. 1H NMR(HCl salt, CDCl₃) δ2.0(br, m,4H, —CH₂CH₂—), 2.9(br, s, 3H, —NCH₃), 6.3(br, m, 1H, —CH),7.2-7.5(complex, 8H, aromatic). MS (FAB) m/z 405. Anal. (C,H,N)C₂₂H₂₆N₃OF₃1.5HCl.

EXAMPLE 952-(2-N,N-Dimethylsulfonamido-2-amino-a,a,a-trifluoro-4-tolyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide;ADL-01-0069-3

Same procedure as 50 using 100 mg(0.24 mmol) of 54, 0.2 mL(2.4 mmol) ofMsCl, 0.8 mL(6.3 mmol) of triethylamine and 13 mL of dry methylenechloride. The crude product was purified by flash chromatography using astepwise gradient of 1% to 5% MeOH:methylene chloride to yield 110mg(80%) of desired product. A small amount of compound was treated with1.0M HCl in diethyl ether to give 55(ADL-01-0069-3) as the HCl salt. ¹HNMR(HCl salt, CDCl₃) δ2.0(br, m, 4H, —CH₂CH₂—), 2.9(s, 3H, —NCH₃),3.3(d, 6H, —(SO₂CH₃)₂), 6.3(br, m, 1H, —CH), 7.1-8.0(complex, 8H,aromatic). MS (FAB) m/z 497. Anal. (C,H,N) C₂₄H₃₀N₃OF₃S₂.HCl.0.5H₂O.

EXAMPLE 962-(N-Methylsulfonamido-2-amino-a,a,a-trifluro-4-tolyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide;ADL-01-0077-6

Same procedure as 51 using 51 mg(0.1 mmol) of 55, 30 mL of 1.0M NaOH and1.9 mL of 2:1 MeOH:THF. The crude product was purified by flashchromatography using a stepwise gradient of 1% to 5% MeOH:methylenechloride with 2% ammonia to yield 27 mg(63%) of pure product which wastreated with 1.0 m HCl in diethyl ether to form 56(ADL-01-0077-6) as theHCl salt. ¹H NMR(HCl salt, CDCl₃) δ2.0(br, m, 4H, —CH₂CH₂—), 2.9(br, s,3H, —NCH₃), 3.1(br, s, 3H, —SO₂CH₃), 7.1-7.3(complex, 8H, aromatic). MS(FAB) m/z 483. Anal. (C,H,N) C₂₃H₂₈N₃O₃SF₃.HCl.0.25H₂O.

EXAMPLE 972-(2-Aminophenyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide;ADL-01-0089-1

Same procedure as 49 using 2.6 g(7.1 mmol) of 40, 2.5 mL(80.2 mmol) ofhydrazine hydrate in 70 mL of EtOH. The recovered product, 1.8 g waspurified by flash chromatography using a stepwise gradient of 1% to 9%MeOH:methylene chloride with 2% ammonia to yield 1.1 g(47%) of pureproduct which was treated with 1.0M HCl in diethyl ether to give57(ADL-01-0089-1) as the HCl salt. ¹H NMR(free base, CDCl₃) δ1.7-1.9(br,m, 4H, —CH₂CH₂—), 2.7(s, 3H, —NCH₃), 6.1(br, m, 1H, —CH),6.5-6.8(complex, 3H, aromatic), 7.0(m, 2H, aromatic), 7.3(complex, 4H,aromatic). MS (FAB) m/z 337. Anal. (C,H,N) C₂₁H₂₇N₃O.2HCl.0.5H₂O.

EXAMPLE 982-(4-Aminophenyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide;ADL-01-0103-0

Same procedure as 49 using 2.3 g(6.3 mmol) of 39, 2.4 mL(75.4 mmol) ofhydrazine hydrate in 70 mL of EtOH. The recovered product, 1.7 g waspurified by flash chromatography using a stepwise gradient of 2% to 3%MeOH:methylene chloride with 2% ammonia to yield 1.53 g(73%) of pureproduct. A small amount of compound was treated with 1.0M HCl in diethylether to give 58(ADL-01-0103-0) as the HCl salt. ¹H NMR(free base,CDCl₃) δ1.8(br, m, 4H, —CH₂CH₂—), 2.7(s, 3H, —NCH₃), 6.1(br, m, 1H,—CH), 6.7(m, 2H, aromatic), 7.0(d, 2H, aromatic), 7.3(complex, 5H,aromatic). MS (FAB) m/z 337. Anal. (C,H,N) C₂₁H₂₇N₃O.2HCl.0.75H₂O.

EXAMPLE 992-(N,N-Dimethylsulfonamido-2-aminophenyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide;ADL-01-0112-1

Same procedure as 50 using 500 mg(1.5 mmol) of 57, 1.1 mL(14.8 mmol) ofMsCl, 3.0 mL(22.2 mmol) of triethylamine and 8.0 mL of dry methylenechloride. The crude product was purified by flash chromatography using astepwise gradient of 1% to 4% MeOH:methylene chloride with 2% ammonia toyield 308 mg(42%) of pure product. A small amount of compound wastreated with 1.0M HCl in diethyl ether to give 59(ADL-01-0112-1) as theHCl salt. ¹H NMR(free base, CDCl₃) δ1.8(br, m, 4H, —CH₂CH₂—), 2.8(s, 3H,—NCH₃), 3.4(s, 6H, (—SO₂CH₃)₂), 6.1(br, m, 1H, —CH), 7.0-7.5(complex,9H, aromatic). MS (FAB) m/z 493. Anal. (C,H,N) C₂₃H₃₁N₃O₅S₂.HCl

EXAMPLE 1002-(N,N-Dimethylsulfonamido-2-aminophenyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide;ADL-01-0127-9

Same procedure as 50 using 400 mg(1.2 mmol) of 58, 0.55 mL(7.1 mmol) ofMsCl, 1.6 mL(11.8 mmol) of triethylamine and 12.0 ml of dry methylenechloride. The crude product was purified by flash chromatography using astepwise gradient of 2% to 5% MeOH:methylene chloride with 2% ammonia toyield 395 mg(68%) of pure product. The compound was treated with 1.0MHCl in diethyl ether to give 60(ADL-01-0127-9) as the HCl salt. ¹HNMR(free base, CDCl₃) δ1.8(br, m, 4H, —CH₂CH₂—), 2.8(s, 3H, —NCH₃),3.4(s, 6H, (—SO₂CH₃)₂), 6.1(br, m, 1H, —CH), 7.0-7.5(complex, 9H,aromatic). MS (FAB) m/z 493. Anal. (C,H,N) C₂₃H₃₁N₃O₅S₂.HCl.0.25H₂O.

EXAMPLE 1012-(2-Hydroxyphenyl)-N-methyl-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide;ADL-01-0061-0

To a solution of 34(700 mg;1.8 mmol) in 10 mL of dry methylene chloride@ −78 degrees was added 10.8 mL(10.8 mmol;1.0M solution of BBr₃ inmethylene chloride) over 15 minutes. The reaction mixture was allowed towarm to room temperature and stir overnight. TLC(95:5 methylenechloride:MeOH w/2% ammonia) indicated no starting material remained. Thereactionn was quenched with the addition of MeOH at 0 degrees. After 30minutes, 3N HCl was added and the mixture was stirred for 30minutes(white precipitate seen). The mixture was made neutral with sat.bicarbonate and extracted with methylene chloride(3×100 MmL). Theorganic layer was dried over anh. sodium sulfate, filtered andconcentrated in vacuo to give 610 mg of crude product. The crude productwas purified by flash chromatography using a stepwise gradient of 2% to3% MeOH:methylene chloride to yield 500 mg(82%) of pure product. Theproduct was treated with 1.0M HCl in diethyl ether to give61(ADL-01-0061-0) as the HCl salt. ¹H NMR(free base, CDCl₃) δ1.7(br, m,4H, —CH₂CH₂—), 2.9(s, 3H, —NCH₃), 6.1(br, m, 1H, —CH), 6.8-7.4(complex,9H, aromatic). MS (FAB) m/z 338. Anal. (C,H,N) C₂₁H₂₆N₂O₂.HCl.0.5H₂O.

EXAMPLE 102N-Methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxypyrrolidine-1-yl)ethyl]-3,4,5-trimethoxyphenylacetamideHCl (A) ADL01-140-2

To a solution of 3,4,5-trimethoxyphenylaetic acid (1.0 g, 4.43 mmol) in10 mL of CH₂Cl₂ under a nitrogen atmosphere was added pyridine (0.12 g,1.5 mmol) and N,N-diisopropylethylamine (Hunig's Base) (0.57 g, 4.43mmol). The reaction mixture was cooled to 0° C. and DCC (1.37 g, 6.65mmol) was added in one portion. The reaction mixture was stirrred atthis temperature and a solution of the diaminel (0.65 g, 3.0 mmol) in 10mL of CH₂Cl₂ was added and the stirring was continued while warming toroom temperature for 20 h. The reaction mixture was poured onto anaqueous saturated solutoin of NaHCO₃ and the mixture was stirred for 30min. The organic layer was separated and dried over anhydrous Na₂SO₄.After removal of the solvent, the product was purifed on a silica gelcolumn [solvent system: CHCl₃:CH₃OH:28%NH₄OH(98:2:2)]. The free base wasconverted to the hydrochloride salt from 1M etherial HCl andrecrystallized form CH₂Cl₂:Et₂O (1:1) to give a HCl 0.64 g (46%) aslight pink solid; mp 230-232° C.; ¹H-NMR (200 MHz, CDCl₃) δ2.20 (m, 4H),2.85 (s, 3H), 3.00-4.30 (m, 5H), 3.70 (ms, 9H), 4.50 (m, 2H), 5.30 (d,J=15.0 Hz, 1H), 6.50 (m, 3H), 7.28 (m, 5H). Anal. Calcd forC₂₄H₃₂N₂O₅.HCl.0.25H₂O: C, 61.40; H, 7.19; N, 5.97. Found: C, 61.36; H,6.84; 8.96; N, 5.91.

The structure of the compound is shown hereunder.

The preparation of compounds of 3a through 3ddd of formula IIIA followaccording to Schemes G, H, I, J, K, L, M, and N.

EXAMPLE (3a)2-(2-N-Methylsulfonamido-4,5-dichlorophenyl-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamidehydrochloride

2-(N,N-Dimethylsulfonamido-2-amino-4,5-dichlorophenyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide(for preparation see U.S. Pat. No. 5,688,955) 130 mg; 0.22 mmol wastreated with 0.2 mL of 10 M NaOH in 3.0 mL of 2:1 MeOH:THF as describedin the preparation of 3rr. The crude product was purified by flashchromatography using a stepwise gradient of 2% to 4% MeOH:methylenechloride with 2% ammonia to give 100 mg (95%) of desired product whichwas treated with 1.0 M HCl to aford 3a as a tan solid. Mp 140-142° C.;1H NMR (HCl salt, DMSO-d₆) δ2.0(br s, 4H, —CH₂CH₂—), 2.8(s, 3H, NCH₃),3.1(s, 3H, SO₂CH₃), 3.6-3.8(m, 2H), 4.0-4.3(q, 2H), 6.0-6.2(dd, 1H),7.2-7.6(complex, 5H), aromatic), 7.7-7.9(d, 2H), 9.5(s, NH). MS(FAB) m/z483. Anal. (C, H, N) Calcd. for C₂₂H₂₉N₃O₃Cl₂SHCl 0.25 H₂O: C, 50.73; H,5.42; N, 8.07. Found: C, 49.32; H, 5.52; N, 7.58.

EXAMPLE (3b)N-[(4-Trifluoromethylphenyl)-N-methyl-N-{[1S]-1-phenyl-2-[1-pyrrolidinyl)]ethyl}acetamido]glycinehydrochloride

To a stirred solution of bromoacetic acid (0.75 g, 5.42 mmol) inanhydrous CH₃CN (20 mL) was added N,N-diisopropylethylamine (1.41 g,11.0 mmol) under a nitrogen atmosphere. After addition of2-(2-Amino-4-trifluoromethylphenyl)-N-methyl-N-{[1S]-1-phenyl-2-[1-pyrrolidinyl)]ethyl}acetamide¹(2.0 g, 4.93 mmol) in anhydrous CH₃CN (10 mL) to the reaction mixture,it was heated to 70° C. for 6 days. TLC [solvent system:CH₂Cl₂:CH₃OH:28% NH₄OH (95:5:2)] of the reaction mixture showed thatstill some starting material was present. The reaction mixture wascooled to room temperature and solvent was evaporated to dryness. Theresidue was partioned between CH₂Cl₂ and water, organic layer wasseparated, dried over anhydrous Na₂SO₄, and evaporated to dryness togive the crude mixture. The residue was crystallized from acetone andacetonitrile (1:1) to give the desired compound as a white solid 0.6 gwhich was still contaminated with minor amounts of the startingmaterial.

Ref

1. U.S. Pat. No. 5,688,955 (1997).

The product 3b was finally purified on Chromatotran (precoated silicaplate) using solvent acetone:water (9:1) and recrystallized fromacetonitrile to give the product as a white solid, 0.35 g (15%); mp228-230° C. (d); MS (FAB) 464 (M+1); ¹H NMR (200 MHz, DMSO-d₆) δ2.16 (m,4H), 2.88 (s, 3H), 3.47-4.00 (m, 9H), 4.50 (m, 1H), 4.95 (m, 1H), 6.34(d, J=9.0 Hz, 1H), 6.82 (d, J=8.0 Hz, 1H), 7.02 (s, 1H), 7.18 (d, J=7.7Hz, 1H), 7.55 (m, 5H). Anal. Calcd. for C₂₄H₂₈F₃N₃O₃.0.25H₂O: C, 61.59;H, 6.14; N, 8.98. Found: C, 61.54; H, 6.10; N, 9.36.

EXAMPLE 3c2-(3,4-Dichlorophenyl)-N-methyl-N-[(1R,S)-1-(3-sulfamidophenyl)-2-(1-pyrrolidinyl)ethyl]acetamidehydrochloride

A solution of compound 1¹ (203 mg, 0.5 mmol) and sulfamide (480 mg, 5mmol) in dioxane (15 ml) was refluxed for 4 hours in oil bath. Afterremoval of dioxane, the residue was partitioned between NaOH (1N, 50 ml)and CHCl₃ (50 ml). The aqueous layer was extracted with CHCl₃ (2×25 ml),and the combined extract was washed with brine, dried (Na₂SO₄). Silicacolumn chromatography of crude material gave a pure product that wasconverted to hydrochloric acid salt with HCl/ether (164 mg, 64%). Mp:198-200° C. Spectral data: ¹H NMR (DMSO-d₆) δ1.97 (m, 4H), 2.80 (s, 3H),3.12 (m, 2H), 3.52-3.66 (m, 3H), 3.72 (d, J=16.5 Hz, 1H), 4.01-4.10 (m,2H), 6.04(d, J=11.0 Hz, 1H), 6.88 (d, J=7.6 Hz, 1H), 6.99 (s, 1H), 7.17(m, 1H), 7.29 (m, 1H), 7.55 (d, J=4.5 Hz, 1H), 9.10 (s, 1H). Fab MS(MH⁺): 485. Anal. Calcd For C₂₁H₂₆N₄O₃Cl₂S.HCl: C, 48.33; H, 5.21; N,10.74. Found: C, 48.31; H, 5.21; N, 10.59.

EXAMPLE 3d2-(4-Trifluoromethylphenyl)-N-methyl-N-{[1S]-1-[3-[(methylsulfonyl)amino]phenyl]-2-[1-pyrrolidinyl]ethyl}acetamidehydrochloride

4-Trifluormethylphenyl acetic acid was condensed with(1S)-1-[2-(methylamino)-2-(3-nitrophenyl)-ethyl]pyrrolidine followingthe methods described in the literature¹ to give the intermediate,3-nitro-derivative in 95% yield, ¹H NMR (200 MHz, CDCl₃) δ1.68 (m, 4H),2.35-3.30 (m, 6H), 2.71 (s, 3H), 3.85 (m, 2H), 6.20 (m, 1H), 7.49 (m,7H), 8.10 (s, 1H). The nitro group was reduced again following themethod described in literature (Raney Ni/hydrazine hydrate) tocorresponding 3-amino derivative in nearly quantitative yield.

To a solution of the above 3-amino compound (2.9 g, 7.15 mmol) in CH₂Cl₂(30 mL) was added triethyl amine (3.62 g, 35.76 mmol) and the reactionmixture was cooled to in an ice-bath. Methane sulfonyl chloride (2.46 g,21.45 mmol) was added dropwise in 15⁻ min and the ice-bath was removed.The reaction mixture was stirred at room temperature for 72 h. Thereaction mixture was quenched with addition of water, organic layer wasseparated, washed with water, saturated NaHCO₃, saturated salt solution,and dried over anhydrous Na₂SO₄. Removal of solvent gave3-N-(bis-methylsulfonamide) derivative as a foam which was used directlyinto the following reaction.

The above compound (4.0 g, 7.12 mmol) was dissolved in CH₃OH:THF (2:1,32 mL) and stirred at room temperature. Sodium hydroxide (10 M aqueoussolution) (1.29 g, 32.26 mmol) was added and stirred at room temperaturefor 20 min [TLC, solvent system: CH₂Cl₂:CH₃H:28% NH₄OH (95:5:2)].Reaction mixture was neutralized with the addition of 1N HCl andevaporated to dryness under reduced pressure. The residue wasredissolved in ethyl acetate, washed with saturated NaHCO₃, saturatedsalt solution, and dried over anhydrous Na₂SO₄. Removal of the solventunder reduced pressure gave a yellow foam which was purified on a silicagel column [solvent system: CH₂Cl₂:CH₃OH:28% NH₄OH (95:5:2)]. Thehydrochloride salt was prepared from 1M etherial HCl and recrystallizedfrom 2-propano:ether (1:1) to give 3d as a cream colored solid in 45%yield; mp 173-175° C.; ¹H NMR (200 MHz, CDCl₃) δ1.65 (m, 4H), 2.30-3.15(m, 6H), 2.67 (s, 3H), 2.86 (s, 3H), 3.80 (m, 2H), 6.05 (m, 1H),7.00-7.25 (m, 4H), 7.35 (d, J=8.2 Hz, 2H), 7.50 (d, J=8.0 Hz, 2H). Anal.Calcd. for C₂₃H₂₈F₃N₃O₃S.HCl.0.5H₂O: C, 55.22; H, 5.72; N, 7.94. Found:C, 52.17; H, 5.61; N, 7.96.

EXAMPLE 3e2-(4-Methanesulfonylphenyl)-N-methyl-N-{[1S]-1-[3-[(methylsulfonyl)amino]phenyl]-2-[1-pyrrolidinyl]ethyl}acetamidemethanesulfonate

The compound was prepared from 4-methylsulfonylphenyl acetic acidfollowing the procedure described for 3d. The methane sulfonic acid saltwas recrystallized from CH₂Cl₂:ether to give 3e as a beige colored solidin 32% yield; mp 140-142° C.; ¹H NMR (300 MHz, DMSO-d₆) δ2.00 (m, 4H),2.40 (s, 3H), 2.78 (s, 3H), 2.97 (s, 3H), 3.20 (s, 3H), 3.40-4.10 (m,6H), 3.94 (d, J=5.5 Hz, 2H), 6.10 (m, 1H), 7.00 (d, J=5.8 Hz, 1H), 7.15(s, 1H), 7.20 (t, J=6.0 Hz, 1H), 7.35 (t, J=5.5 Hz, 1H), 7.50 (d, J=12.5Hz, 2H), 7.85 (d, J=12.0 Hz, 2H). Anal. Calcd. for C₂₃H₃₁N₃O₅S₂.CH₃SO₃H.2.0H₂O: C, 46.06; H, 6.28; N, 6.71. Found: C, 45.99; H, 6.03; N, 6.55.

EXAMPLE 3f2-(3,4-Dichlorophenyl)-N-methyl-N-{[1S]-1-[3-[(methylsulfonyl)amino]phenyl]-2-[1-pyrrolidinyl]ethyl}acetamidehydrochloride

2-(3,4-Dichlorophenyl)-N-methyl-N-{[1S]-1-[3-(bis-methylsulfonyl)amino]phenyl]-2-[1-pyrrolidinyl]ethyl}acetamide¹(1.8 g, 3.2 mmol) was dissolved in CH₃OH:THF (2:1, 90 mL) and added 10 MNaOH solution (0.58 g, 14.5 mmol). The reaction was followed by TLC[solvent system:CH₂Cl₂:CH₃OH:28% NH₄OH (95:5:2)] and worked up asdescribed in case of 3d to give the crude product as a foam. Thecompound was purified on a silica gel column [solventsystem:CH₂Cl₂:CH₃OH:28% NH₄OH (95:5:2)] and the hydrochloride salt wasprepared from 1M etherial HCl. Recrystallization of the salt fromCH₂Cl₂:ether (1:1) gave 3f as a beige colored solid, 0.57 g (35%); mp240-242° C. Anal. Calcd. for C₂₂H₂₇Cl₂N₃O₃S.HCl.0.25H₂O: C, 50.29; H,5.47; N, 8.00. Found: C, 50.63; H, 5.26; N, 7.66

EXAMPLE 3g 2-(3,4-Dichlorophenyl)-N-methyl-N-[(1S)-1-[3-(3diethylphosphoryl)amino]phenyl)-2-(1-pyrrolidinyl)ethyl]acetamide hydrochloride

2-(3,4-Dichlorophenyl)-N-methyl-N-{[1S]-1-(3-aminophenyl)-2-[1-pyrrolidinyl]ethyl}-acetamide¹(0.411 g, 1.011 mmol) was dissolved in anhydrous THF (8 mL) and cooledin an ice-bath under a nitrogen atmosphere. Diisopropylethylamine (1.06mL, 6.07 mmol) was added followed diethyl chlorophosphate (0.58 mL,4.045 mmol). The reaction mixture was stirred at room temperature for 48h, quenched with the addition of water, and evaporated to dryness. Theresidue was partitioned between CH₂Cl₂ and saturated NaHCO₃ solution.The organic layer was separated, dried over anhydrous sodium sulphate,and evaoparted under reduced pressure to give the crude product. Thecompound was purified on a silica gel column [solventsystem:CH₂Cl₂:CH₃OH:28% NH₄OH (99:1:2)] and converted to thehydrochloride salt from 1M etherial HCl to give 3g, 0.44 g (81%); mp140-142° C.; ¹H NMR (200 MHz DMSO-d₆) δ1.18 (t, J=8.0 Hz, 3H), 1.95 (m,4H), 2.77 (s, 3H), 3.00-4.20 (m, 12H), 6.05 (m, 1H), 6.75 (d, J=8.0 Hz,1H), 6.88 (s, 1H), 7.00 (d, J=7.5 Hz, 1H), 7.25 (m, 2H), 7.53 (m, 2H),8.05 (d, J=8.6 Hz, 1H). Anal. Calcd. for C₂₅H₃₄Cl₂N₃O₄P.HCl.0.5H₂O: C,51.07; H, 6.17; N, 7.15. Found: C, 50.91; H, 5.93; N, 6.97.

EXAMPLE 3h2-(3,4-Dichlorophenyl)-N-methyl-N-[(1S)-1-[3-[(4-oxo-butenoate)]amino]phenyl)-2-(1-pyrrolidinyl)ethyl]acetamide

2-(3,4Dichlorophenyl)-N-methyl-N-{[1S]-1-(3-aminophenyl)-2-[1-pyrrolidinyl]ethyl}-acetamide¹(0.0.347 g, 0.855 mmol) was dissolved in anhydrous THF (8 mL) under anitrogen atmosphere and added a solution of maleic anhydride (0.084 g,0.855 mmol) in anhydrous THF (1 mL) at room temperature. The reactionmixture was stirred at this temperature for 24 h and the resulting solidwas filtered, washed with THF and ether. The solid was dried undervacuum to give 3h, (0.274 g, 63%); mp 174-176° C.; MS 504 (m/z); ¹H NMR(200 MHz, DMSO-d₆) δ1.79 (m, 4H), 2.72(s, 3H), 2.85-3.85 (m, 6H), 5.95(m, 1H), 6.10 m, 1H), 6.25 (m, 1H), 6.95 (d, J=8.0 Hz, 1H), 7.28 (m,2H), 7.55 (m, 4H). Anal. Calcd. for C₂₅H₂₇Cl₂N₃O₄.0.25H₂O: C, 59.00; H,5.45; N, 8.26. Found: C, 58.69; H, 5.18; N, 8.01.

EXAMPLE 3i2-(3,4-Dichlorophenyl)-N-methyl-N-{(1S)-1-[3-(3-(((iso-butoxycarbonyl)-methyl)aminocarbonyl)propionamido)phenyl]-2-(1-pyrrolidinyl)ethyl}acetamidehydrochloride

A solution of compound 1 (222 mg, 0.546 mmol) in CH₂CL₂ (10 ml) at 0° C.was treated with succinic anhydride (82 mg, 0.819 mmol). The mixture wasallowed to warm up to room temperature and stirred for 18 hours. Thesolvent was removed by rotary evaporation and the residue wasrecrystallized from ethyl acetate and hexane (249 mg, 89%). A mixture ofthe above compound (246 mg, 0.486 mmol), 1-hydroxybenzotriazolemonohydrate (98 mg, 0.729 mmol), and p-toluenesulfonic acid salt of2-methylpropyl glycine (221 mg, 0.729 mmol) in THF (5 ml) was treatedwith Et₃N (0.102 ml, 0.729 mmol), followed by dicyclohexylcarbodiimide(150 mg, 0.729 mmol) in THF (2 ml). The mixture was stirred at roomtemperature for 48 hours, cooled in ice bath, and filtered. The filtratewas concentrated, dissolved in ethyl acetate, and the solution waswashed with aqueous NaHCO₃ (saturated), water, brine, dried (Na₂SO₄).After concentration, the residue was allowed to pass through a silicacolumn eluted with 2% MeOH in CH₂Cl₂ (2% ammonia). 216 mg of the desiredproduct was obtained (72%) and part of the product was converted to thehydrochloric acid salt (compound 3i, 67 mg). Mp: 85° C. (decomposed).Spectral data: ¹H NMR (DMSO-d₆) δ0.86 (d, J=6.7 Hz, 6H), 1.84 (m, 1H),1.97 (m, 4H), 2.40-2.50 (m, 4H), 2.77 (s, 3H), 3.14 (m, 1H), 3.47-3.70(m, 3H), 3.75-3.83 (m, 5H), 3.98-4.14 (m, 2H), 6.06 (d, J=10.0 Hz, 1H),6.93 (d, J=7.7 Hz, 1H), 7.30 (m, 2H), 7.50-7.57 (m, 4H), 8.37 (bs, 1H).Fab MS (MH⁺): 485. Anal. Calcd for C₃₁H₄₀N₄O₅C₁₂.HCl.1.2 H₂O: C, 54.94;H, 6.46; N, 8.27. Found: C, 54.94; H, 6.43; N, 8.28.

EXAMPLE 3j2-(3,4-Dichlorophenyl)-N-methyl-N-{(1R,S)-1-[3-(3-(((hydroxycarbonyl)-methyl)aminocarbonyl)propionamido)phenyl]-2-(1-pyrrolidinyl)ethyl}acetamidehydrochloride

A solution of compound 3i (144 mg, 0.233 mmol) in ethanol (3 ml) andwater (1 ml) was cooled in ice bath and treated with NaOH (1N, 0.7 ml)slowly. After stirring at room temperature for 1 hour, the solution wasadjusted to pH=5 with 6N HCl. The mixture was stirred for 2 hours andthen concentrated. The residue was separated by reversed phase TLC plateto give the final product (114 mg, 80%). Mp: 158° C. (decomposed).Spectral data: ¹H NMR (DMSO-d₆) δ1.65 (bs, 4H), 2.40-2.64 (m, 4H), 2.70(s,3H), 3.11 (m,2H), 3.33 (m, 2H), 3.71 (m, 3H), 3.86 (d, J=16.0 Hz,1H), 5.81 (dd, J=9.9, 4.9 Hz, 1H), 6.94 (d, J=8.1 Hz, 1H), 7.23 (t,J=7.8 Hz, 1H), 7.48-7.56 (m, 4H), 8.17 (bs, 1H), 9.95 (s, 1H). Fab MS(MH⁺): 563. Anal. Calcd for C₂₇H₃₂N₄O₅Cl₂.HCl.0.75H₂O: C, 52.79; H,5.68; N, 9.12. Found: C, 52.83; H, 5.92; N, 9.10.

EXAMPLE 3k2-[(2-N-Phenylsulfonamido)-phenyl]-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamidemethane sulfonate

2-(2-Aminophenyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide(for preparation see U.S. Pat. No. 5,688,955) 1.2 g(3.55 mmol) wasstirred in 30 mL of dry CH₂Cl₂ at 0° C. Triethylamine (0.5 mL; 3.55mmol) and benzenesulfonyl chloride (0.45 mL; 3.55 mmol) in 10 mL of dryCH₂Cl₂ were added. After the addition the reaction solution was allowedto warm to room temperature and stirred overnight. TLC (90:10 methylenechloride:methanol w/2% ammonia) indicated the reaction was incomplete.0.22 mL (1.7 mmol) of the chloride and 0.25 mL (1.7 mmol) of the basewere added at 0° C. The solution was stirred for 24 h at roomtemperature before it was complete. The reaction was quenched with sat.sodium bicarbonate and the layers were separated. The organic layer waswashed with brine, dried (Na₂SO₄), filtered and concentrated in vacuo togive 1.9 g of crude product which was purified by flash chromatographyusing a stepwise gradient of 2% to 7% MeOH:methylene chloride w/2%ammonia to yield 1.2 g of bis-alkylated product which was hydrolyzedusing the same preparation as 3rr to afford 900 mg (53%) of desiredproduct which was treated with 1.0 eq. of methanesulfonic acid to give3k as a tan solid. mp 205-207° C.; ¹H NMR (mesylate salt, CDCl₃) δ1.8(brm, 1H), 2.1(br d, 2H), 2.2(br t, 2H), 2.8(s, 3H, NCH₃), 3.1(t, 1H),4.0-4.3(d, 2H), 6.2(dd, 1H), 7.0(d, 2H), 7.1(m, 2H), 7.30 (complex, 5H,aromatic), 7.4(d, 1H), 7.5(d,1H), 7.9(d, 2H), 9.0(s, 1H), 10.3(br, NH).MS(FAB) m/z 477. Anal. (C,H,N) Calcd. for C₂₇H₃₁N₃O₃SCH₃SO₃H: C, 58.62;H, 6.15; N, 7.32. Found: C, 58.66; H, 6.20; N, 7.27.

General Procedure for the Preparation of N-methyl sulfamoyl Derivativesof phenyl acetic acids

To a stirred ice-cold chlorosulfonic acid (43.82 g, 0.376 mol) underanhydrous condition was added dropwise methyl phenylacetate (6.23 g,0.042 mol). When addition was completed, the reaction mixture was thenstirred at room temperature and the progress of the reaction wasmonitored by TLC [solvent: hexane:ethyl acetate (4:1)] [In this case thereaction was over in 30 min and however depending upon the substitution(X=H) of the aromatic ring, reaction may take from 12 to 72 h at roomtemperature]. Reaction mixture was then carefully poured on ice-waterand the product was extracted with ether several times. The combinedetherial solution was washed with water, saturated salt solution, anddried over anhydrous sodium sulfate. Removal of ether under reducedpressure resulted in a mixture of 2- and 4-chlorosulfonyl compounds(63-85% yields) (chlorosulfonation was also depended upon the directingeffects of the X group) which were used directly into next reaction.

To a stirred solution of methyl amine (19.5 ml, 2 M in THF, 0.039 mol)at 0° C. under a nitrogen atmosphere was added a solution of abovechlorosulfonyl derivative (3.25 g, 0.013 mo) in anhydrous THF (10 mL).Reaction mixture was stirred 15 min at this temperature and 1-4 h atroom temperature by this time TLC [solvent: hexane:ethyl acetate (4:1)]showed no starting material was present. The solvent was removed underreduced pressure and the residue was partioned between ethyl acetate andwater. The organic layer was separated washed with saturated saltsolution, dried over anhydrous sodium sulfate, and evaporated to drynessto give methyl sulfonamide derivative (90-96% yield). In most cases thisproduct was pure enough to proceed to next step, otherwise purified on asilica gel column before the hydrolysis of the ester.

The methyl sulfonamide ester (3.0 g, 12.34 mmol) was suspended in 3Naqueous HCl and heated to reflux with stirring for 24 h. The solvent wasremoved under reduced pressure and the residue was re-dissolved inCH₂Cl₂, filtered, and concentrated to a small volume. Addition of eitherether or hexane gave compound A in 80-95% yield and these acids wereused in the condensation reactions.

EXAMPLE 3l2-[3-(N-Methylsulfamoyl)-4-chlorophenyl]-N-methyl-N-{[1S]-1-phenyl-2-[1-pyrrolidinyl]ethyl}acetamidehydrochloride

To a solution of 3-(N-methylsulfamoyl)-4-chlorophenyl acetic acid(prepared from 4-chlorophenyl acetic acid, 1.58 g, 6.0 mmol) inanhydrous CH₂Cl₂ (20 mL) under a nitrogen atmosphere was addN-hydroxybezotriazole (0.81 g, 6.0 mmol). Reaction mixture was stirredat room temperature for 15 min then cooled in an ice-bath and added1-(3-diethylaminoprpyl)-3-ethylcarbodiimide hydrochloride (1.165 g, 6.0mmol). Stirring was continued at ice-bath temperature for 30 min thenadded a solution of (1S)1-[(2-methylamino-2-phenyl)ethyl]pyrrolidine¹(1.02 g, 5.0 mmol) in anhydrous CH₂Cl₂ (10 mL) followed byN,N-diisopropylethylamine (0.79 g, 6.1 mmol). Reaction mixture wascontinued stirring for 48 h [TLC, solvent system: CH₂Cl₂:CH₃OH:28% NH₄OH(95:5:2)]. After addition of more CH₂Cl₂, the organic phase was washedwith water, saturated sodium bicarbonate solution, saturated saltsolution, and dried over anhydrous sodium sulfate. Removal of thesolvent under reduced pressure gave the crude product which was covertedto the hydrochloride salt from 1M etherial HCl. The salt wasre-crystallized from 2-prppanol to give 3l as off-white solid, 1.52 g(62%); 285-287° C.; ¹H NMR (300 MHz, DMSO-d₆) δ2.01 (m, 4H), 2.50 (d,J=4.5 Hz, 3H), 2.87 (s, 3H), 3.17(m, 2H), 3.64 (m, 3H), 3.90 (d, J=10.0Hz, 1H), 4.14 (d, J=10.5 Hz, 2H), 6.20 (m, 1H), 7.28-7.45 (m, 4H),7.55-7.65 (m, 3H), 7.90 (d, J=3.5 Hz, 1H). Anal. Calcd. forC₂₂H₂₈CIN₃O₃S.HCl.0.75H₂O: C, 52.85; H, 6.15; N, 8.40. Found: C, 52.84;H, 5.89; N, 8.40.

EXAMPLE 3m2-(3-Sulfamoyl-4-chlorophenyl)-N-methyl-N-{[1S]-1-phenyl-2-[1-pyrrolidinyl]ethyl}acetamidemethanesulfonate

Prepared from 3-sulfonamido-4-chlorophenyl acetic acid following theabove procedure and the free base was converted to methanesulfonic acidsalt. Recrystallization from 2-propanol gave 3m as a white solid in 51%yield; mp 220-222° C.; MS (FAB) 436 (M+1); ¹H NMR (300 MHz, DMSO-d₆)δ2.00 (m, 4H), 2.36 (s, 3H), 2.76 (s, 3H), 3.20 (m, 2H), 3.50-3.80 (m,4H), 3.94 (bs, 2H), 6.15 (m, 1H), 7.25 (d, J=6.0 Hz, 1H), 7.30-7.65 (m,6H), 7.88 (d, J=2.5 Hz, 1H). Anal. Calcd. for C₂₁H₂₆CIN₃O₃S.CH₃SO₃H: C,49.66; H, 5.68; N, 7.90. Found: C, 49.69; H, 5.63; N, 7.78.

EXAMPLE 3n2-(3-Sulfamoyl-4-chlorophenyl)-N-methyl-N-{[1S]-1-[3-[(methylsulfonyl)amino]phenyl]-2-[1-pyrrolidinyl]ethyl}acetamidemethanesulfonate

(S)-1-[2-(Methylamino)-2-(3-nitrophenyl)ethyl]pyrrolidine¹ was condensedwith 3-sulfonamido-4-chlorophenyl acetic acid following the generalprocedure described in 83% yield. The catalytic reduction of the 3-nitrogroup was done with PtO₂ to give the 3-amino intermediate.Bis-mesylation of the 3-amino group followed by selective removal one ofthe mesyl group as described for 3d resulted in the desired compound in28% yield. Methanesulfonic acid salt was prepared in 71% yied to give3n; mp 170-173° C.; MS (FAB) 543 (M+1); ¹H NMR (300 MHz, DMSO-d₆) δ1.98(m, 4H), 2.35 (s, 3H), 2.44 (d, J=5.0 Hz, 3H), 2.77 (s, 3H), 2.98 (s,3H), 3.10-4.15 (m, 6H), 3.90 (d, J=8.0 Hz, 2H), 6.20 (m, 1H), 7.00-7.75(m, 6H), 7.90 (d, J=2.0 Hz, 1H). Anal. Calcd. forC₂₃H₃₁CIN₄O₅S₂.CH₃SO₃H.0.5H₂O: C, 44.47; H, 5.60; N, 8.64. Found: C,44.26; H, 5.53; N, 8.45.

EXAMPLE 3o2-[3-(N-Methylsulfamoyl)-4-fluorophenyl]-N-methyl-N-{[1S]-1-phenyl-2-[1-pyrrolidinyl]ethyl}acetamidehydrochloride

Prepared from 3-methylsulfonamido-4-fluorophenyl acetic acid followingthe above procedure to give 3o as a white solid in 85% yield; mp278-280° C.; ¹H NMR (free base, 200 MHz, CDCl₃) δ1.73 (m, 4H), 2.61 (bs,3H), 2.68 (s, 3H), 2.90-3.20 (m, 2H), 3.55-3.90 (m, 3H), 4.75 (b, 1H),6.05 (m, 1H), 7.05-7.60 (m, 7H), 7.72 (bd, 1H). Anal. Calcd. forC₂₂H₂₈FN₃O₃S.HCl: C, 516.22; H, 6.22; N, 8.94. Found: C, 56.22; H, 6.24;N, 8.86.

EXAMPLE 3p and 3r2[2&4-(N-Methylsulfamoyl)-phenyl]-N-methyl-N-[(1S)-1-phenyl-2-[1-pyrrolidinyl)ethyl]acetamidehydrochloride

Compounds 3p and 3r were prepared using the general EDCI/DIPEA couplingprocedure of (1S)-N-methyl-2-pyrrolidino-1-phenethylamine (1.3 g; 6.34mmol), a mixture of 2 and 4 substituted reversed sulfamides acids (1.6g; 6.98 mmol), HOBT (943 mg; 6.9 mmol), EDCI (1.33 g; 6.98 mmol) andDIPEA (1.32 mL; 7.60 mmol). After 24 hours, TLC (95:5 methylenechloride:methanol with 2% ammonia) indicates the reaction is complete.After the standard work-up, the crude product was purified using astepwise gradient of 2% to 10% MeOH:methylene chloride with 2% ammoniato afford 1.6 g of a mixture of the 2 and 4 substituted sulfamideproducts. The mixture was separated using a stepwise gradient of 1% to2% MeOH:methylene chloride with 2% ammonia on a chromatotran to afford14 mg (0.5%) of the 2-substituted compound 3p and 20 mg (0.7%) of the4-substituted compound 3r, which were converted to the HCl salt with 1.0M HCl in diethyl ether. ¹H NMR (HCl salt, CDCL₃) δ1.7(br s, 4H,—CH₂CH₂—), 2.4-2.6(m, 2H), 2.6(d, 3H, NHCH₃), 2.8(s, 3H, NCH₃),3.0-3.3(t, 2H), 3.8(d, 2H), 6.0-6.2(dd, 1H), 7.2-7.4(complex, 5H,aromatic), 7.5-7.7(m, 2H), 7.8(s, 2H). MS(FAB) m/z 415.

EXAMPLE 3q3-(N-Methylsulfamoyl)-phenyl-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamidehydrochloride

Compound 3q was prepared using the HOBT/EDCI coupling proceduredescribed in U.S. Pat. No. 5,885,955 with 3-SO₂NHCH₃ phenyl acetic acid(A) 2.23 g; 9.73 mmol, (1S)-N-methyl-2-pyrrolidino-1-phenethylamine(1.90g; 9.26 mmol), HOBT (1.31 g;9.73 mmol), EDCI (1.85 g; 9.73 mmol) andDIPEA (3.38 mL; 19.46 mmol). The crude product was purified by flashchromatography using a stepwise gradient of 2% to 8% MeOH:methylenechloride with 2% ammonia to give 1.40 g (40%) of desired product whichwas treated with 1.0 M HCl in diethyl ether to afford 3q as the HClsalt. mp >250° C.(dec.); ¹H NMR (HCl salt, CDCl₃ with 3 drops of CD₃OD)δ2.0-2.2(br, 4H, —CH2CH₂—), 2.6(s, 3H, NHCH₃), 2.8(s, 3H, NCH₃),3.4-3.5(d, 2H), 6.3-6.4(dd, 1H), 7.2(d, 2H), 7.3-7.4(complex, 5H,aromatic), 7.5(t, 1H), 7.6(d, 1H), 7.7(d, 1H), 7.8(s, 1H). MS(FAB) m/z415. Anal. (C,H,N) Calcd. for C₂₂H₂₉N₃O₃S.HCl: C, 58.46; H, 6.69; N,9.30. Found C, 59.34; H, 6.62; N, 9.19.

EXAMPLE 3s2-[N-Methylsulfamoyl-4-bromo-phenyl]-N-methyl-N-[(1S)-1-phenyl-2-[1-pyrrolidinyl]ethylacetamide hydochloride

Compound 3s was prepared using the HOBT/EDCI coupling proceduredescribed in U.S. Pat. No. 5,885,955 using 2-SO₂NHCH₃, 4-bromorphenylacetic acid (2.3 g;7.40 mmol),(1S)-N-methyl-2-pyrrolidino-1-phenethylamine (1.4 g;7.08 mmol), HOBT(1.0 g;7.46 mmol), EDCI (1.4 g;7.46 mmol)and DIPEA (1.5 mL; 8.95 mmol).The crude product was purified by flash chromatography-using a stepwisegradient of 2% to 8% MeOH:methylene chloride with 2% ammonia to give 500mg, (30%) of 3s as the desired product which was treated with 1.0 M HClin diethyl ether to afford the HCl salt. mp >280° C.; MS(FAB) m/z 494.Anal. (C,H,N) Calcd. for C₂₂H₂₈N₃O₃SBr.HCl.0.5H₂O: C, 49.77; H, 5.51; N,7.91. Found: C, 48.86; H, 5.36; N, 7.67.

EXAMPLE 3t2-[2&4-(N-Methylsulfamoyl)phenyl]-N-methyl-N-{[1S]-1-phenyl-2-[1-(3S)-3-hydroxypyrrolidinyl]ethyl}acetamidehydrochloride

Prepared from A (X=H) and(1S)1-[(2-methylamino-2-phenyl)ethyl](3S)-3-hydroypyrrolidine¹ as anon-separable mixture of 2- and 4-sustituted methylsulfonamido compound3t in 16% yield; mp 1448-150° C.; ¹H NMR (free base, 200 MHz, CDCl₃)δ1.73 (m, 2H), 2.52 (bs, 3H), 2.66 (s, 3H), 2.10-3.40 (m, 6H), 3.76-3.81(m, 3H), 4.20 (m, 1H), 6.00 (m, 1H), 7.15-7.55 (m, 8H), 7.70-7.82 (bd,2H). Anal. Calcd. for C₂₂H₂₉N₃O₄.HCl: C, 55.92; H, 6.51; N, 8.89. Found:C, 55.90; H, 6.03; N, 8.49.

EXAMPLE 3u2-[2-Methoxy-3-(N-methylsulfamoyl)phenyl]-N-methyl-N-{[1S]-1-phenyl-2-(1-pyrrolidinyl)ethyl}acetamidehydrochloride

The compound 3u was prepared in 49% yield from2-methoxy-3-(N-methylsulfamoyl)phenyl acetic acid following the generalprocedure; mp 278-280° C.; ¹H NMR (free base, 200 MHz, CDCl₃) δ1.77 (m,4H), 2.48 (d, J=5.2 Hz, 3H), 2.82 (s, 3H), 2.50-3.90 (m, 6H), 3.67 (d,J=10.5 Hz, 1H), 3.87 (s, 3H), 3.92 (d, J=11.0 Hz, 1H), 4.75 (m, 1H),6.05 (m, 1H), 6.95 (d, J=8.5 Hz, 1H), 7.22-7.37 (m, 5H), 7.71-7.75 (m,2H). Anal. Calcd. for C₂₃H₃₁N₃O₄S.HCl: C, 57.31; H, 6.69; N, 8.72.Found: C, 57.47; H, 6.64; N, 8.73.

EXAMPLE 3v(Z)-4-[2-(2-Aminophenyl)-N-methyl-N-[(1S)-1-phenyl)-2-[1-(3S)-3-hydroxypyrrolidinyl]-ethyl]acetamido]4-oxo-2-butenoicacod

To a solution ofN-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxypyrrolidine-1-yl)ethyl]-2-aminophenylacetamide²(0.5 g, 1.42 mmol) in anhydrous THF (5 mL) under a nitrogen atmospherewas added maleic anhydride (0.139 g, 1.42 mmol) at room temperature for48 h. The resulting dark solution was diluted with anhydrous ether. Theresulting solid was filtered, washed thoroughly with ether, and dried togive 3v (0.55 g, 87%); mp 172-174° C. (d); ¹H NMR (200 MHz, DMSO-d₆)δ2.00-2.25 (m, 3H), 2.85 (s, 3H), 3.25-4.30 (m, 8H), 4.50 (m, 1H), 5.95(d, J=12.5 Hz, 1H), 6.20 (m, 1H), 6.35 (d, J=12.8 Hz, 1H), 7.15-7.67 (m,8H), 7.80 (d, J=6.5 Hz, 1H). Anal. Calcd. for C₂₅H₂₉N₃O₅.0.75H₂O: C,64.57; H, 6.61; N, 9.04. Found: C, 64.33; H, 6.40; N, 8.83.

Ref.

2. Gottschlich R. et. Al. BioOrg. Med. Chem. Lett., 4, 677-682 (1994)

EXAMPLE 3w(Z)-4-[2-(2-Amino-4,5-dichlorophenyl)-N-methyl-N-[(1S)-1-phenyl)-2-[1-pyrrolidinyl]ethyl]acetamido]4-oxo-butanoicacid

To a solution of2-(2-Amino-4,5-dichlorophenyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)-ethyl]acetamide¹(0.86g, 2.0 mmol) in anhydrous THF under a nitrogen atmosphere was addedsuccinic anhydride (0.25 g, 2.5 mmol). The reaction mixture was stirredat room temperature for 96 h and added excess of anhydrous ether. Theresulting solid was filtered off, washed with ether and dried to givecrude product. The compound was purified on a silica gel column(acetone:water, 9:1). The desired compound was re-dissolved in CH₂Cl₂,filtered, and concentrated to a small volume. Addition of ether resultedthe solid which was filtered, washed with ether, and dried to give 3w(0.32 g, 30%); mp 168-170° C.; ¹H NMR (300 MHz, CDCl₃) δ2.03 (m, 4H),2.36 (m, 1H), 2.66 (m, 2H), 2.81 (s, 3H), 2.80-2.95 (m, 2H), 3.10 (m,1H), 3.40 (d, J=14.0 Hz, 1H), 3.67 (d, J=14.5 Hz, 1H), 4.18 (t, J=12.0Hz, 1H), 6.40 (d, J=11.5 Hz, 1H), 7.20 (m, 3H), 7.45 (m, 3H), 8.00 (s,1H). Anal. Calcd. for C₂₅H₂₉Cl₂N₃O₄S₂.0.5H₂O: C, 58.26; H, 5.87; N,8.15. Found: C, 58.08; H, 5.75; N, 7.96.

EXAMPLE 3x(Z)-4-[2-(2-Amino-4,5-dichlorophenyl)-N-methyl-N-[(1S)-1-phenyl)-2-[1-pyrrolidinyl]-ethyl]acetamido]4-oxo-2-butenoicacid

To a solution of2-(2-amino-4,5-dichlorophenyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)-ethyl]acetamide¹(0.8g, 1.85 mmol) in anhydrous THF (10 mL) under a nitrogen atmosphere wasadded maleic anhydride (0.181 g, 1.85 mmol) and the stirred at roomtemperature for 4 days. After addition of anhydrous ether, the resultingsolid was sonicated and filtered. Recrystallization of the solid fromCH₂Cl₂:ether (1:1) gave 3x (0.51 g, 52% yield); mp 158-160° C. (d); ¹HNMR (200, MHz, CDCl₃) δ2.00 (m, 4H), 2.72 (s, 3H), 2.75-3.20 (m, 2H),3.35 (d, J=12.5 Hz, 1H), 3.85 (d, J=13.0 Hz, 1H), 3.90-4.20 (m, 2H),6.10 (d, J=12.5 Hz, 1H), 6.25 (m, 2H), 7.15 (m, 3H), 7.44 (m, 3H), 8.00(s, 1H). Anal. Calcd. for C₂₅H₂₇Cl₂N₃O₄.0.25H₂O: C, 59.00; H, 5.45; N,8.26. Found: C, 59.20; H, 5.57; N, 7.90.

EXAMPLE 3y(E)Ethyl4-[2-(2-amino-4,5-dichlorophenyl)-N-methyl-N-[(1S)-1-phenyl)-2-[1-pyrrolidinyl]ethyl]acetamido]4-oxo-2-butenoatehydrochloride

To a solution of fumaric acid monoethyl ester (1.30 g, 9.02 mmol) inanhydrous CH₂Cl₂ (20 mL) under anitrogen atmosphere was added DCC (1.86g, 9.03 mmol) followed by pyridine (0.43 mL, 5.31 mmol). The reactionmixture was stirred at room temperature for 30 min then added a solutionof2-(2-amino-4,5-dichlorophenyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)-ethyl]acetamide¹(2.30g, 5.31 mmol) in anhydrous CH₂Cl₂ (10 mL). The reaction mixture wasstirred at this temperature for 72 h, filtered and evaporated to drynessto give the crude product. The compound was purified on asilica gelcolumn [solvent system: CH₂Cl₂:CH₃OH:28% NH₄OH (99:1:2)] to give thefree base of the desired product. The hydrochloride salt was preparedfrom 1M etherial HCl and recrystallized from CH₂Cl₂:ether (1:1) to give3y (2.0 g, 60%); mp 165-1670° C. (d); ¹H NMR (300, MHz, CDCl₃) δ1.28 (t,J=7.0 Hz, 3H), 2.00-2.40 (m, 4H), 2.89 (s, 3H), 2.96 (m, 2H), 3.28 (m,1H), 3.50 (m, 2H), 3.95-4.10 (m, 4H), 4.21 (q, J=7.1 Hz, 2H), 4.50 (d,J=15.0 Hz, 1H), 6.33 (d, J=10.0 Hz, 1H), 6.89 (d, J=15.0 Hz, 1H),7.10-7.40 (m, 5H), 7.93 (d, J=15.3 Hz, 1H), 8.43 (s, 1H). Anal. Calcd.for C₂₇H₃₁Cl₂N₃O₄.HCl.H₂O: C, 55.25; H, 5.84; N, 7.16. Found: C, 55.63;H, 5.73; N, 6.94.

EXAMPLE 3z(Z)-4-[2-(2-Amino-4-trifluoromethylphenyl-N-methyl-N-[(1S)-1-phenyl)-2-[1-pyrrolidinyl]-ethyl]acetamido]4-oxo-2-butenoicacid

The compound 3z was prepared from2-(2-amino-4-trifluoromethylphenyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)-ethyl]acetamide¹following the above in 40% yield; mp 153-155° C. (d); MS (FAB) 504(M+1); ¹H NMR (200, MHz, DMSO-d₆) δ2.01 (m, 4H), 2.85 (s, 3H), 2.85-3.30(m, 2H), 3.40 (d, J=14.5 Hz, 1H), 3.95 (d, J=14.0 Hz, 1H), 4.10 (m, 2H),6.30 (m, 3H), 7.18 (m, 3H), 7.38 (m, 4H), 8.15 (s, 1H). Anal. Calcd. forC₂₆H₂₈F₃N₃O₄.0.75H₂O: C, 60.40; H, 5.75; N, 8.13. Found: C, 60.07; H,5.50; N, 7.91.

EXAMPLE 3aa(Z)-4-[2-(2-Aminophenyl)-N-methyl-N-[(1S)-1-phenyl)-2-[1-pyrrolidinyl]-ethyl]acetamido]4-oxo-2-butenoicacid hemimaleate

The compound 3aa was prepared from2-(2-aminophenyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)-ethyl]acetamide¹following the above in 93% yield; mp 149-151° C.; Anal. Calcd. forC₂₅H₂₉N₃O₄.0.5C₄H₄O₄.H₂O: C, 63.39; H, 6.50; N, 8.21. Found: C, 63.37;H, 6.20; N, 8.22.

EXAMPLE 3bb 2-(N,N-Bisaceticacid-2-amino-ααα-trifluro-4-tolyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamidehydrochloride

2-(2-Amino,α,α,α-trifluoro-4-toly)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]-acetamide(for the preparation see U.S. Pat. No. 5,688,955) 2.0 g; 4.93 mmol wasdissolved in 50 ml of dry THF at 0° C. DIPEA (5.15 mL; 29.6 mmol) andt-butyl bromoacetate (3.64 ml; 24.65 mmol) were added 15 minutes apart.The reaction was allowed to warm to room temperature and stirred for 4days. TLC (95:5 methylene chloride:methanol with 2% ammonia) indicatedthe reaction is incomplete. Added 1.67 mL (9.58 mmol) of DIPEA to thereaction. After 24 hours the reaction mixture was concentrated to aresidue. The residue was dissolved in methylene chloride and washed withsat. sodium bicarbonate and brine. The organic layer was dried (anh.Na₂SO₄), filtered and concentrated in vacuo to give a yellow oil. Thecrude product was purified by flash chromatography using a stepwisegradient of 1% to 8% MeOH:methylene chloride with 2% ammonia to afford1.2 g (61%) of bis-alkylated material which was used in the next step[¹H NMR, (Free base, CDCl₃) δ1.4 (s, 9H, t-butyl), 1.5(s, 9H, t-butyl,1.7-1.9(m, 4H), 3.2(s, 3H NCH₃), 3.6-3.7(dd, 4H), 4.3-4.8(q, 4H),5.7-5.9(dd, 1H), 6.0(d, 1H), 6.4(d, 1H), 6.6(s, 1H), 6.9-7.2(m, 2H),7.4(complex, 3H, aromatic). MS(FAB) m/z 633. The bis-alkylated compound(1.2 g; 1.89 mmol) was stirred in 33 mL of glacial acetic acid with 4drops of anisole. After 60 hours, the reaction was concentrated invacuo. The residue was dissolved in acetonitrile and added drop-wise toa solution of 1.0 M HCl in diethyl ether. The precipitate was collectedby filtration and dried at 40° C. under vacuum to yield 960 mg (93%) of3bb as a tan solid. mp 166-169° C.; ¹H NMR (HCl salt, DMSO-d₆) δ1.6(brs, 4H, —CH₂CH₂—), 2.9(s, 3H, NCH₃), 3.8(q, 4H0, 4.1-4.3(d, 2H),4.7-4.9(m, 3H), 6.6br, d, 1H), 7.1(s, 1H), 7.4(d, 1H), 7.6(d, 1H),7.7-8.0(complex, 5H, aromatic). MS(FAB) m/z 521. Anal. (C,H,N) Calcd.for C₂₆H₃₀N₅O₃F₃.2HCl.H₂O: C, 58.46; H, 6.69; N, 9.30. Found: C, 58.40;H, 6.65; N, 9.21.

EXAMPLE 3cc3-[2-N-Methylsulfonamido)-phenyl]-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamidehydrochloride

Compound 3cc was prepared using the same procedure as described in thepreparation of compound(2-N-Methylsulonamido-2-aminophenyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide(forthe preparation see U.S. Pat. No. 5,688,955). Compound3-(N,N-Dimethylsulfonamido-2-aminophenyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide(1.0 g; 2.02 mmol), 10 mL of 10 M NaOH and 30 mL of 2:1 MeOH:THF. Thecrude product was clean by TLC and ¹H NMR (760 mg; 90%). The product wastreated with 1.0 M HCl in diethyl ether to give 3cc as the HCl salt; mp155-160° C.(dec.); ¹H NMR (Free base, CDCl₃) δ1.7(br s, 4H, —CH₂CH₂—),2.5(br d, 2H), 2.8(s, 3H, NCH₃), 2.9(s, 3H, SO₂CH₃), 3.7(d, 2H),6.0-6.1(dd, 1H), 7.0-7.4(complex, 9H, aromatic). MS(FAB) m/z 415. Anal.(C,H,N) Calc. for C₂₂H₂₉N₃O₃S.HCl: C, 58.46; H, 6.69; N, 9.30. Found: C,58.40; H, 6.65; N, 9.21.

EXAMPLE 3dd2-(O-Butylacetate)-phenyl-N-methyl-N-[(1S)-1-phenyl-2-[1-pyrrolidinyl]ethylacetamide hydrochloride

2-(2-Hydroxyphenyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide(for preparation see U.S. Pat. No. 5,688,955,) 1.3 g;(3.80 mmol) wasdissolved in 10 mL of dry THF and added to a 0° C. slurry of NaH (95%,10 mg; 4.03 mmol) in dry THF. The mixture was allowed to warm to roomtemperature for 30 minutes, then cooled to 0° C. Ethyl bromoacetate(0.44 mL; 4.03 mmol) was added drop-wise over a few minutes. After 30minutes, the mixture was warmed to room temperature and stirred for 5days. TLC(95:5 methylene chloride:methanol with 2% ammonia) indicatedthe reaction was complete. The reaction was quenched with sat. ammoniumchloride and concentrated in vacuo. The residue was dissolved inmethylene chloride and separated from water. The organic layer waswashed with brine, dried (anh. Na₂SO₄), filtered and concentrated invacuo to give 1.61 g of crude product, which was purified by flashchromatography using a stepwise gradient of 2% to 9% MeOH:methylenechloride with 2% ammonia to afford 1.0 g (70%) of 3dd as a desiredproduct, which was treated with 1.0 M HCl in diethyl ether to give theHCl salt. mp 184-187° C.; ¹H NMR (HCl salt, CDCl₃) 1.2(t, 3H),1.7-1.9(br, s, 4H, —CH₂CH₂—), 2.0(br d, 2H), 2.2-2.5(m, 2H), 2.8-3.0(m,2H), 3.0(s, 3H, NCH₃), 3.3-3.5(t, 1H), 4.0-4.1(m, 2H), 4.2(q, 2H),6.2-6.3(dd, 1H), 6.8(d, 1H), 6.9-7.1(t, 1H), 7.2-7.5(complex, 7H,aromatic). MS(FAB) m/z 424. Anal. (C,H,N) Calcd. forC₂₅H₃₂N₂O₄.HCl.0.5H₂O: C, 65.14; H, 7.22; N, 6.08. Found: C, 63.70; H,7.00; N, 6.09.

EXAMPLE 3ee2-[Phenoxy-acetyl]methylamino-(1-pyrrolidinyl)ethyl]acetamide]hydrochloride

2-(2-Hydroxyphenyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide(for the preparation see U.S. Pat. No. 5,688,955) 960 mg; 2.83 mmol wasdissolved in 6.0 mL of dry THF and added to a slurry of NaH (95%) 79 mg;3.12 mmol in dry THF at 0° C. The mixture was allowed to warm to roomtemperature and stirred for 30 minutes, then cooled to 0° C. whent-butyl bromoacetate (0.42 ml; 2.83 mmol) in 2 mL of dry THF was addeddrop-wise. The solution was allowed to warm to room temperature andstirred overnight. TLC (95:5 methylene chloride:methanol w/2% ammonia)indicated the reaction was complete. The reaction was quenched withsaturated ammonium chloride and concentrated in vacuo. The residue wasdissolved in methylene chloride and separated from water. The organiclayer was washed with brine, dried (anh. Na₂SO₄), filtered, andevaporated to give a brown residue. The crude product was purified byflash chromatography using a stepwise gradient of 1% to 8%MeOH:methylene chloride with 2% ammonia to afford 900 mg (70%) ofdesired compound; ¹H NMR, (Free base, CDCl₃) δ1.4(s, 9H, t-butyl),2.7-2.9(br s, 4H), 2.7(s, 3H), 3.8(s, 2H), 4.5(s, 2H), 6.1-6.2(dd, 1H),6.7-6.8(d, 2H), 6.9-7.0(t, 3H), 7.1-7.4 (complex, 5H, aromatic), MS(FAB)m/z 452] which was used in the next step by adding 4.0 mL of 4N HCl, 4drops of anisole and stirring overnight at room temperature. TLCindicated the reaction was incomplete. The solution was heated to 50° C.for 24 hours. The reaction mixture was concentrated in vacuo and theresidue was azeotroped with toluene. The crude product was dissolved intriturated with diethyl ether to give 730 mg (93%) of 3ee as the freeacid; mp 105-108° C.; ¹H NMR (HCl salt, DMSO-d₆) δ1.9-2.4(br s, 4H,—CH₂CH₂—), 2.9(s, 3H, NCH₃)3.8-4.1(m, 3H), 4.5-4.7(d, 2H), 6.2(dd, 1H),6.8(d, 1H), 6.9(t, 1H), 7.1-7.3(complex, 7H, aromatic). MS(FAB) m/z 396.Anal (C,H,N) Calc. for C₂₃H₂₈N₂O₄.HCl.0.75H₂O: C, 63.81; H, 6.75; N,6.47. Found C, 61.87; H, 6.84; N, 6.19.

EXAMPLE 3ff2-[4-Trifluoromethylphenyl]-N-methyl-N-{[1S]-1-phenyl-2-[1-(3S)-3-hydroxypyrrolidinyl]ethyl}acetamidehydrochloride

The compound 3ff was prepared fromN-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxypyrrolidine-1-yl)ethyl]-2-aminophenylacetamide²and 4-trifluoromethylphenyl acetic acid in 54% yield; mp 217-219° C.(d); ¹H NMR (free base, 200, MHz, CDCl₃) δ1.88 (m, 2H), 2.35 (m, 3H),2.85 (s, 3H), 2.50-3.35 (m, 4H), 3.98 (m, 2H), 4.10 (m, 1H), 6.00 (m,1H), 7.30 (m, 5H), 7.55 (d, J=9.0 Hz, 2H), 7.77 (d, J=9.5 Hz, 2H). Anal.Calcd. for C₂₂H₂₅F₃N₂O₂.HCl: C, 59.66; H, 5.92; N, 6.32. Found: C,59.45; H, 5.68; N, 5.98.

EXAMPLE 3gg2-(2-Pyridyl)-N-methyl-N-{[1S]-1-phenyl-2-[1-(3S)-3-hydroxypyrrolidinyl]ethyl}acetamidedihydrochloride

The compound 3gg was prepared as above from 2-pyridyl acetic acid in 38%yield; mp 180-182° C. (d); ¹H NMR (free base, 200, MHz, CDCl₃) δ1.78 (m,2H), 2.10-2.65 (m, 3H), 2.75 (s, 3H), 2.88-3.20 (m, 4H), 3.95 (d, J=13.0Hz, 1H), 4.10 (d, J=13.5 Hz, 1H), 4.20 (m, 1H), 6.05 (m, 1H), 7.20 (m,7H), 7.60 (t, J=7.0 Hz, 1H), 8.35 (d, J=6.5 Hz, 1H). Anal. Calcd. forC₂₀H₂₅N₃O₂.2HCl.0.25H₂O: C, 57.63; H, 6.65; N, 10.8. Found: C, 57.73; H,6.79; N, 9.83.

EXAMPLE 3hh2-(5-Bromo-3-pyridyl)-N-methyl-N-[(1S)-1-phenyl-2-pyrrolidinylethyl]acetamidehydrochloride

Compound 3hh was prepared using the general EDCI/DIPEA couplingprocedure from U.S. Pat. No. 5,688,955 with,(1S)-N-methyl-2-pyrrolidino-1-phenethylamine (200 mg; 0.98 mmol),5-bromo-3-pyridylacetic acid (231 mg; 1.07 mmol), HOBT (145 mg; 1.07mmol), EDCI (204 mg; 1.07 mmol), and DIPEA (0.26 mL; 1.47 mmol). Thereaction solution was allowed to stir at room temperature overnight. TLC(95:5 methylene chloride:methanol with 2% ammonia) indicated thereaction was complete. The reaction was quenched with sat. sodiumbicarbonate and the layers were separated. The organic layer was washedwith brine and dried (anh. Na₂SO₄), filtered and evaporated. The crudeproduct was purified by flash chromatography using a stepwise gradientof 2% to 4% MeOH:methylene chloride with 2% ammonia to afford 337 mg(85%) of pure product which was treated with 1.0 M HCl in diethyl etherto give 3hh as the HCl salt; mp 228-230° C.; ¹H NMR (HCl salt, DMSO-d₆)δ2.0 (br s, 4H, —CH₂CH₂—), 2.8 (s, 3H, NCH₃), 4.1-4.2 (br m, CH₂),6.1-6.2 (br d, 1H, CH), 7.2-7.5 (complex, 5H, aromatic), 8.0-8.1(br s,1H, pyridyl), 8.5 (s, 1H, pyridyl), 8.6 (s, 1H, pyridyl); MS(FAB) m/z401. Anal. (C,H,N) Calcd. for C₂₀H₂₄N₃OBr.HCl: C, 54.75; H, 5.74; N,9.58. Found: C, 54.66; H, 5.71; N, 9.41.

EXAMPLE 3ii2-(5-Bromo-3-pyridyl)-N-methyl-N-{[1S]-1-phenyl-2-[1-(3S)-3-hydroxypyrrolidinyl]ethyl}acetamidehydrochloride

The compound 3ii was prepared from 5-bromo-3-pyridyl acetic acidfollowing the procedures described above in 44% yield; mp 144-146° C.;¹H NMR (free base, 200, MHz, CDCl₃) δ1.66 (m, 2H), 2.00-2.50 (m, 3H),2.77(s, 3H), 2.88-3.40 (m, 4H), 3.80(d, J=13.0 Hz, 1H), 3.95 (d, J=13.5Hz, 1H), 4.35 (m, 1H), 6.15 (m, 1H), 7.20 (m, 5H), 7.75 (s, 1H), 8.50(s, 1H), 8.85 (s, 1H). Anal. Calcd. for C₂₀H₂₄BrN₃O₂.HCl.0.25H₂O: C,51.79; H, 5.65; N, 9.06. Found: C, 51.96; H, 5.55; N, 8.76.

EXAMPLE 3jj2-(9-Anthracenyl)-N-methyl-N-{[1S]-1-phenyl-2-(1-pyrrolidinyl)ethyl}acetamidehydrochloride

The compound 3jj was prepared from 9-anthracene carboxylic acid as abovein 34% yield; mp 273-275° C.; ¹H NMR (200, MHz, CDCl₃) δ2.00 (m, 4H),2.67 (s, 3H), 3.00 (m, 1H), 3.45 (m, 1H), 3.88 (m, 1H), 4.40 (m, 2H),5.80 (m, 1H), 7.43 (m, 8H), 7.88 (m, 5H), 8.38 (s, 1H). Anal. Calcd. forC₂₈H₂₈N₂O.HCl.0.25H₂O: C, 74.82; H, 6.61; N, 6.23. Found: C, 75.00; H,6.60; N, 6.26.

EXAMPLE 3kk2-(2-Carboxyphenyl)-N-methyl-N-{[1S]-1-phenyl-2-(1-pyrrolidinyl)ethyl}acetamidehydrochloride

To a solution of (S)-1-[(2-methylamino-2-phenyl)ethyl]pyrrolidine¹ (1.0g, 5.21 mmol) in anhydrous THF (5 mL) under a nitrogen atmosphere wasadded homophthalic anhydride (0.845 g, 5.21 mmol) and the reactionmixture was stirred at room temperature for 4 days. The resulting solidwas filtered, washed with THF and HCl salt was prepared by usual fashionto give 3kk (1.0 g, 50%); mp 230-232° C. (d); MS (FAB) 367 (M+1); ¹H NMR(200, MHz, DMSO-d₆) δ2.07 (m, 4H), 2.92 (s, 3H), 3.30-3.98 (m, 5H), 4.00(d, J=14.0 Hz, 1H), 4.18 (m, 1H), 4.43 (d, J=14.0 Hz, 1H), 6.15 (m, 1H),7.30-7.65 (m, 8H), 8.00 (d, J=8.0 Hz, 1H). Anal. Calcd. forC₂₂H₂₆N₂O₃.HCl: C, 65.58; H, 6.75; N, 6.96; Cl, 8.81. Found: C, 65.52;H, 6.81; N, 7.04; Cl, 8.81.

EXAMPLE 3ll[2-(2-Phenyl)-N-methyl-N-{[1S]-1-phenyl-2-(1-pyrrolidinyl)ethyl}acetamido]2-oxo-glycinehydrochloride

To a suspension of 3ff was condensed with glycine t-butyl esterhydrochloride following the general procedure to give the intermediatein 55% yield. The t-butyl group was removed by 4N HCl to give thedesired product which was recrystallized from acetonitrile to give 3llin 93% yield; mp 235-236° C.; MS (FAB) 424 (M+1); ¹H NMR (200, MHz,DMSO-d₆) δ1.95 (m, 4H), 2.72 (s, 3H), 3.35-4.25 (m, 11H), 6.18 (m, 1H),7.20-7.65 (m, 8H), 8.70(m, 1H). Anal. Calcd. for C₂₄H₂₉N₃O₄.HCl.0.75H₂O:C, 60.88; H, 6.71; N, 8.87. Found: C, 60.97; H, 6.65; N, 8.91.

EXAMPLE 3mm MethylN-[2(2-pheny)-N-methyl-N-{[1S]-1-phenyl-2-pyrrolidinyl)ethyl}acetamido]2-oxo-glycinatehydrochloride

To a solution of 3ff(0.50 g, 1.05 mmol) in anhydrous methanol (50 mL)was added Dowex® 50Wx4-400 (H⁺) resin (5.0 g, pre-washed with methanol).The reaction mixture was the stirred with refluxing under a nitrogenatmosphere for 48 h. The resin was removed by filtration washed withexcess of hot methanol and the combined mehanolic solution wasevaporated to dryness. The residue was redissolved in CH₂Cl₂ andconcentrated to a small volume and addition of anhydrous ether resultedthe compound 3mm (0.12 g, 24%); mp 204-206° C.; MS (FAB) 438 (M+1); ¹HNMR (200, MHz, CDCl₃) δ1.85-2.45 (m, 6H), 2.75-3.25 (m, 2H), 2.92 (s,3H), 3.75 (s, 3H), 3.80-4.25 (m, 7H), 6.25 (bs, 1H), 7.15-7.77(m, 9H).Anal. Calcd. for C₂₅H₃₁N₃O₄.HCl.0.25H₂O: C, 62.75; H, 6.85; N, 8.78.Found: C, 62.65; H, 6.87; N, 8.60.

EXAMPLE 3nn2-(3,4-Dihydroxyphenyl)-N-methyl-N-{[1S]-1-phenyl-2-(1-pyrrolidinyl)ethyl}acetamidehydrochloride

The compound was prepared from 3,4-dihydroxyphenyl acetic acid in 12%yield; mp 227-229° C. (d); ¹H NMR (300, MHz, DMSO-d₆) δ1.90 (m, 4H),2.70 (s, 3H), 3.05-3.20 (m, 2H), 3.35 (bs, 2H), 3.45-3.70 (m, 4H), 4.50(m, 1H), 6.12 (m, 1H), 6.45 (d, J=8.1 Hz, 1H), 6.62 (m, 2H), 7.18 (d,J=7.5 Hz, 2H), 7.32 (m, 3H), 8.73 (bs, 1H), 8.83 (bs, 1H). Anal. Calcd.for C₂₁H₂₆N₂O₃.HCl.0.25H₂O: C, 63.79; H, 7.01; N, 7.08. Found: C, 63.59;H, 6.89; N, 7.15.

EXAMPLE 3oo2-(3,4-Dimethoxyphenyl)-N-methyl-N-{[1S]-1-phenyl-2-(1-pyrrolidinyl)ethyl}acetamidehydrochloride

The compound was prepared from 3,4-dimethoxyphenyl acetic acid in 65%yield; mp ; 240-242° C.; ¹H NMR (300, MHz, CDCl₃) δ2.00-2.35 (m, 4H),2.85(s, m, 5H), 3.26 (m, 1H), 3.18 (s, m, 7H), 4.05 (m, 4H), 6.36 (m,1H), 6.81 (m, 2H), 6.93 (s, 1H), 7.19 (m, 2H), 7.36 (m, 3H). Anal.Calcd. for C₂₃H₃₀N₂O₃.HCl: C,; H, 7.01; N, 7.08. Found: C, 63.59; H,6.89; N, 7.15.

EXAMPLE 3pp2-(2-Methanesulfonamidophenyl)-N-methyl-N-[(1S)-1-(3-methanesulfon-amidophenyl)-2-(1-pyrrolidinyl)ethyl]acetamideHydrochloride (1)2-(2-Nitrophenyl-N-methyl-N-[(1S)-1-(3-nitrophenyl-2(1-pyrrolidinyl)-ethyl]acetamide

A solution of 2-nitrophenylacetic acid (1.99 g, 11.0 mmol) and1-hydroxybenzotriazole (1.49 g, 11.0 mmol) in CH₂CL₂ (50 ml) was cooledin an ice bath. To this slurry was added EDCI, and the solution turnedbrown clear after 30 minutes at room temperature. A solution of(2s)-1-[2-methylamino)-2-(3-nitrophenyl)ethyl]pyrroli-dine¹ (2.49 g,10.0 mmol) in CH₂Cl₂ (5 ml) was added, followed by DIPEA. The solutionwas stirred in ice bath for 30 minutes and then at room temperature for18 hours. The reaction was quenched by adding saturated aqueous NaHCO₃(20 ml) and stirred for 10 minutes. After separation, the organic layerwas washed with water, brine, dried (Na₂SO₄). The solvent was removedvia rotary evaporation and the brown residue was purified by silicacolumn chromatography [2% MeOH/CH₂Cl₂ (2%NH₃)] to give the product (2.4g, 58%).

(2)2-Aminophenyl-1-N-methyl-N-[(1R,S)-1-(3-aminophenyl)-2-(1-pyrrolidinyl)ethyl]acetamide

A suspension of above compound (475 mg, 1.15 mmol) and Raney nickel (50%slurry in water) in ethanol (10 ml) was heated at 50° C. and treatedwith a solution of hydrazine hydrate (360 ml, 11.5 mmol) in ethanol (2ml). Upon addition of the reagent, effervescent occurred. The mixturewas then stirred at 50° C. for 0.5 h. After cooling, the mixture wasfiltered through a bed of celite, and the catalyst was washed with hotmethanol (10 ml). The combined filtrate and washing was evaporated anddried in vacuum (388 mg, 95%). ¹H NMR (DMSO-d₆): δ1.64 (bs, 4H), 2.40(bs, 2H), 2.58 (m, 2H), 2.66 (s, 3H), 3.06-3.59 (m, 4H), 4.95 (s, 2H),5.01 (s, 2H), 5.77 (dd, J=4.9, 11.4 Hz, 1H), 6.39-6.48 (m, 4H), 6.63 (d,J=7.6 Hz, 1H), 6.89-7.04 (3H).

To a solution of the diamine (388 mg, 1.11 mmol) in CH₂Cl₂ (10 ml)cooled in an ice bath was added pyridine (540 ml, 6.67 mmol), followedby MsCl (190 ml, 2.45 mmol) in CH₂Cl₂ (5 ml). The mixture was stirred at0° C. for 0.5 h and then at room temperature for 18 hours. The solutionwas washed with saturated aqueous NaHCO₃ (2×50 ml), brine, dried(Na₂SO₄). The solvent was removed by rotary evaporation and the residuewas purified by silica column chromatography to give gummy foam afterdrying (383 mg, 68%) which was then converted to the HCl salt formMp:160° C. (d). ¹H NMR (DMSO-d₆): δ1.96 (bs, 4H), 2.77 (s, 3H), 2.97 (s,3H), 2.98 (s, 3H), 3.14 (m, 2H), 3.57 (m, 3H), 3.97-4.10 (m, 3H), 6.12(d, J=10.8 Hz, 1H), 7.03-7.37 (m, 8H), 9.10 (s, 1H), 9.81 (s, 1H). FabMS (MH⁺): 509. Anal. Calcd. for C₂₃H₃₃N₄O₅S₂Cl: C, 48.47; H, 6.43; N,9.50. Found: C, 48.57; H, 6.07; N, 9.25.

EXAMPLE 3qq2-(2-Iso-butyramidophenyl)-N-methyl-N-[(1S)-1-(3-isobutyramido-phenyl)-2-(1-pyrrolidinyl)ethyl]acetamideMethanesulfonic acid salt

To a solution of the diamine (132 mg, 0.376 mmol) in CH₂Cl₂ (5 ml)cooled in an ice bath was added pyridine (182 mL 2.26 mmol), followed byisobutyryl chloride (119 ml, 1.14 mmol) in CH₂Cl₂ (5 ml). The mixturewas stirred at 0° C. for 0.5 h and then at room temperature for 18hours. The solution was washed with aqueous saturated NaHCO₃ (2×25 ml),brine, dried (Na₂SO₄). TLC indicated that the compound was contaminatedby bis-acylated side product. Thus, the solvent was removed by rotaryevaporation and the residue was dissolved in MeOH (2 ml), treated with adrop of NaOH (13 N), and stirred at room temperature for 5 minutes.After neutralization with HCl (6N), the solvent was evaporated, theresidue was purified by silica column chromatography to give a gummyfoam after drying which was then converted to methanesulfonic acid salt(178 mg, 76%). Mp:143-145° C.; ¹H NMR (DMSO-d₆): δ1.08 (m, 12H), 1.88(m, 2H), 2.00 (m, 2H), 2.31 (s, 3H), 2.56 (m, 2H), 2.65 (s, 3H), 3.18(m, 2H), 3.36-3.63 (m, 6H), 3.80 (d, J=16.2 Hz, 1H), 4.10 (m, 1H), 6.09(d, J=10.8 Hz, 1H), 6.90 (d, J=7.6 Hz, 1H), 7.10-7.63 (m, 7H), 9.20 (bs,1H), 9.41 (s, 1H), 9.92 (s, 1H). Fab MS (MH⁺): 493. Anal. Calcd. forC₃₀H₄₄N₄O₆S: C, 58.86; H, 7.67; N, 9.15. Found: C, 58.77; H, 7.51; N,8.98.

EXAMPLE 3rr4[4-N-Methylsulfonamido-phenyl]-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)-ethyl]acetamidehydrochloride

4-(N,N-Dimethylsulfonamido-2-aminophenyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide(for preparation see U.S. Pat. No. 5,688,955) 1.3 g; 2.63 mmol wasdissolved in 60 mL of 2:1 MeOH:THF and 2.0 mL of 10 M NaOH was added.After 20 minutes, TLC (95:5 methylene, chloride:methanol with 2%ammonia) indicated the reaction was complete. The reaction wasneutralized with 10% HCl and concentrated in vacuo. The residue wasdissolved in methylene chloride and washed with 10% sodium bicarbonate,brine and dried (anh. Na₂SO₄). The organic layer was concentrated invacuo and the crude product was purified by flash chromatography using astepwise gradient of 2% to 8% MeOH:methylene chloride with 2% ammonia togive 300 mg (28%) of desired product, which was treated with 1.0 M HClin diethyl ether to afford 3rr as a tan solid. mp >260° C.(dec.); ¹H NMR(HCl salt, DMSO-₆) δ2.0 (br s, 4H, —CH₂CH₂—), 2.8(s, 3H, NCH₃), 3.0(s,3H), SO₂CH₃), 3.8-4.0(m, 2H), 6.1-6.3(dd, 1H), 7.1-7.5(complex, 9H,aromatic), 9.7(s, 1H). MS(FAB) m/z 415. Anal. (C,H,N) Calcd. forC₂₂H₂₉N₃O₃S.HCl.0.25 H₂O: C, 58.46; H, 6.69; N, 9.30. Found: C, 57.89;H, 6.64; N, 9.19.

EXAMPLE 3ss2-(3,4-Dichlorocinnamyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)-ethyl]acetamidehydrochloride

The compound was prepared from 3,4-dichlorocinnamic acid in 70% yield;mp 220-222° C.; Anal. Calcd. for C₂₂H₂₄Cl₂N₂O.HCl: C, 60.08; H, 5.73; N,6.37. Found: C, 60.25; H, 5.81; N, 6.28.

EXAMPLE 3tt2-(2-Nitrocinnamyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamidehydrochloride

The compound was prepared from 2-nitrocinnamic acid in 46% yield; mp195-197° C.; Anal. Calcd. for C₂₂H₂₅N₃O₃.HCl: C, 63.53; H, 6.30; N,10.10. Found: C, 63.25; H, 6.38; N, 10.08.

EXAMPLE 3uu(R,S)-1-[2-(Methanesulfonylamino)phenyl-N-methylacetamido]-1-(3-methoxyphenyl)-2-(1-pyrrolidino)-ethane,methanesulfonic acid salt (R,S)-3-Methoxy-phenylglycine (5, Scheme M)

NaCN (12.2 g, 0.249 mol) was dissolved in 50 ml of water, and to thissolution was added ammonium chloride (13.3 g, 0.249 mol). When all haddissolved, a solution of m-anisaldehyde (33.8 g, 0.249 mol) in 50 ml ofEtOH was added slowly. The mixture was stirred at ambient temperaturefor 2-3 hours. TLC indicated no starting material left. The mixture wastaken up in water/toluene (50 ml/50 ml). The organic layer was washedwith water (50 ml), extracted with 6N HCl (2×30 ml). To hydrolyze theamino cyanide, the hydrochloric extract was refluxed for 4˜5 hours. Thesolution was cooled to room temperature and filtered from some tarrymaterial. The filtrate was cooled in ice bath and the aminoacid salt wascollected via filtration, washed with cold water (20 ml), ether, driedat 60 degrees overnight to give 5 (14.5 g, 27%); NMR (DMSO-d₆), δ3.7(3H, s), 4.29 (1H, s), 6.87 (1H, m), 6.96 (1H, d, J=7.6 Hz), 6.98 (1H,s), 7.26 (1H, t, J=8.0 Hz).

(R,S)-N-Methoxycarbonyl-2-(3-methoxyphenyl)glycine (6)

R,S-3-Methoxy-phenylglycine (5, 14.5 g, 66.7 mmol) was dissolved in NaOH(1N, 233 ml, 233 mmol) and the solution was cooled in ice bath for 15minutes. To this solution was added methyl chloroformate (7.73 ml, 100mmol) dropwise. After the addition was complete, the mixture was stirredat room temperature for 2 hours. The pH was adjusted to 10 with 2N NaOHand the stirring was continued for 1 hour. The solution was washed withether (2×100 ml), acidified with 6N HCl after addition of EtOAc (100ml). The aqueous layer was extracted with EtOAc (100 ml), and thecombined organic extracts were washed with brine (100 ml), dried over(Na₂SO₄), concentrated to yellow syrup 6, (14.4 g, 90%). NMR (CDCl₃),δ3.70 (3H, s), 3.82 (3H, s), 5.35 (1H, d), 5.77 (1H, d), 6.87-7.01(3H,m), 7.31(1H, t).

(R,S)-Methoxycarbonyl-2-(3-methoxyphenyl)glycine, pyrrolidine (7)

R,S-N-Methoxycarbonyl-2-(3-methoxyphenyl) glycine (6, 14.4 g, 60.4 mmol)and HOBt (8.97 g, 66.4 mmol) were dissolved in THF (150 ml) and cooledin ice bath. To this solution was added a solution of DCC (12.4 g, 60.4mmol) in THF (50 ml). After stirring at room temperature for 2 hours,the mixture was cooled in ice bath, and the resulting DCU was filtered,washed with cold THF. The filtrate was treated with a solution ofpyrrolidine (5.0 ml, 60.4 mmol) in dichloromethane (50 ml). The solutionwas stirred at room temperature for 18 hours and concentrated. Theresidue was taken up in EtOAc (250 ml), and the mixture was washed withNaHCO₃ (saturated, 200 ml), water, brine, dried over Na₂SO₄,concentrated to a pale solution (50 ml) which was stored in refrigeratorovernight. The more precipitated DCU was filtered off and the filtratewas dried to give a pale yellow oil 7, (12.8 g, 77%). NMR (CDCl₃), δ1.8(4H, m), 3.4-3.6 (4H, m), 3.65 (3H, s), 3.8 (3H, s), 5.35 (1H, d)6.8-7.0 (3H, m), 7.3 (1H, m).

(R,S)-(3-Methoxyphenyl)-1-methylamino-2-(1-pyrrolidino)ethane (8)

LiAlH₄ (5.3 g, 140 mmol) was stirred in anhydrous THF (200 mL) under N₂and a solution of R,S-N-Methoxycarbonyl-2-(3-methoxyphenyl) glycine,pyrrolidine (12.8 g, 46.6 mmol) in THF (100 ml) was added over 30minutes at 10˜15 degree. The mixture was stirred at room temperature for0.5 hour then at 55 degree for 2 hours. After cooling in ice bath themixture was carefully quenched with excess saturated NaHCO₃, filtered.The filtrate was washed with brine, dried over Na₂SO₄, and evaporated to10.0 grams of colorless oil (8) that was used in further reactionwithout purification.

(R,S)-1-(2-Nitrophenyl-N-methylacetamido)-1-(3-methoxyphenyl)-2-(1-pyrrolidino)-ethane(9)

A solution of 2-Nitrophenylacetic acid (1.99 g, 11.0 mmol), HOBt (1.49g, 11.0 mmol) in THF (50 ml) was cooled in ice bath and treated with asolution of DCC (2.27 g, 11.0 mmol) in THF (5 ml). The mixture waswarmed up to room temperature and stirred for 2 hours. After cooling inice bath the precipitated DCU was filtered, and the filtrate was treatedwith a solution ofR,S-1-(3-Methoxyphenyl)-1-methylamino-2-(1-pyrrolidino) ethane (8) inCH₂Cl₂ (10 ml). The solution was stirred in N₂ at room temperature for18 hours and concentrated. The residue was dissolved in EtOAc (100 ml),washed with saturated NaHCO₃, brine, dried (Na₂SO₄). Removal of thesolvent, followed by silica column chromatography yielded 3.0 grams ofthe product (9). NMR (CDCl₃), a 1.74 (4H, bs), 2.52 (2H, bs), 2.67 (2H,bs), 2.77 (1H, m), 2.84 (3H, s), 3.10 (1H, m), 3.83 (3H, s), 4.02-4.31(2H, m), 6.03 (1H, dd, J=6.0, 9.8 Hz), 6.80-6.94 (3H, m), 7.26 (1H, m),7.39-7.46 (2H, m), 7.54-7.59 (1H, m), 8.10 (1H, dd, J=1.2, 8.0 Hz).

(R,S)-1-(2-Aminophenyl-N-methylacetamido)-1-(3-methoxyphenyl)-2-(1-pyrrolidino)-ethane

A suspension ofR,S-1-(2-nitrophenyl-N-methylacetamido)-1-(3-methoxyphenyl)-2-(1-pyrrolidino)-ethane(8) (1.3 g, 3.27 mmol) and Raney Ni (1 spatula) in EtOH (20 ml) wasstirred at 50 degree and treated with a solution of hydrazine hydrate inEtOH (10 ml). After effervescent stopped, the mixture was stirred at 55degree for 0.5 hour, then cooled to room temperature, filtered through abed of celite, washed with hot MeOH (20 ml). The combined filtrate andwashing was concentrated, dried to yellow residue (1.2 g) of aminocompound that was used with further purification.

(R,S)-1-[2-(Methanesulfonylamino)phenyl-N-methylacetamido]-1(3-methoxyphenyl)-2-(1-pyrrolidino)-ethane,methanesulfonic acid salt (3uu)

To a solution ofR,S-1-(2-aminophenyl-N-methylacetamido)-1-(3-methoxyphenyl)-2-(1-pyrrolidino)-ethane(1.2 g, 3.24 mmol) in CH₂Cl₂ (20 ml) was added pyridine (0.79 ml, 9.72mmol), followed by a solution of MsCl (0.376 ml. 4.86 mmol). The mixturewas stirred at room temperature for 18 hours. The mixture was washedwith water (20 ml), brine, dried Na₂SO₄). The solution was concentrated,and the residue was purified via silica column chromatography to give ayellowish oil (1.20 g, 83%). 251 mg of the free base was converted tomethane sulfonic acid salt, 3uu. Mp: 135° C. (decomposed). NMR(DMSO-d₆), δ1.92 (2H, bs), 2.02 (2H, bs), 2.32 (3H, s), 2.72 (3H, s),2.97 (3H, s), 3.19 (2H, m), 3.56-3.97 (8H, m), 4.03-4.12 (2H, m), 6.08(1H, d, J=12.0 Hz), 6.74 (1H, s), 6.81 (1H, dd, J=2.3, 8.0 Hz),7.16-7.39 (5H, m), 9.07 (1H, s), 9.26 (1H, bs). MS (FAB) m/z 446. Anal.(C, H, N) C₂₃H₃₁N₃O₄S.CH₃SO₃H.0.2H₂O.

EXAMPLE 3vv(R,S)-1-[2-(Methanesulfonylamino)phenyl-N-methylacetamido]-1-(3-hydroxyphenyl)-2-(1-pyrrolidino)-ethane,methanesulfonic acid salt

A solution ofR,S-1-[2-(Methanesulfonylamino)phenyl-N-methylacetamido]-1-(3-methoxyphenyl)-2-(1-pyrrolidino)-ethane(3uu, 196 mg, 0.440 mmol) in CH₂Cl₂ (15 ml) was cooled to −70 degree andtreated with a solution of BBr₃ (1.0 M in CH₂Cl₂, 1.45 ml, 1.45 mmol) inCH₂Cl₂ (2 ml). The mixture was stirred at −70 degree for 1 hour, thenslowly warmed up to room temperature overnight. The mixture wascarefully quenched at 0 degree with MeOH (5 ml) and the solution wasevaporated under reduced pressure. The residue was stirred in 10 ml ofanhydrous MeOH/Et₂O (1/1) for 6 hours and filtered. The white solid wastaken up in CHCl₃ (50 ml) and NaHCO₃/Na₂CO₃ (pH˜10)(50 ml). The organiclayer was washed with brine, dried (Na₂SO₄). After removal of thesolvent, the residue was dissolved in MeOH (5 ml)-and treated withCH₃SO₃H (0.026 ml, 0.404 mmol). The solvent was evaporated and theresidue was sonicated in ether. The precipitate was filtered, dried togive 3vv, (0.164 g, 84%). Mp: 232-234° C. NMR (DMSO-d₆), δ1.93 (2H, bs),2.02 (2H, bs), 2.32 (3H, s), 2.70 (3H, s), 2.97 (3H, s), 3.16 (2H, bs),3.40-3.80 (4H, m), 4.03-4.12 (2H, m), 6.04 (1H, d, J=9.6 Hz), 6.63-6.72(3H, m), 7.14-7.39 (5H, m), 9.06 (1H, s), 9.21 (1H, bs), 9.56 (1H, s).MS (FAB) m/z 432. Anal. (C, H, N) C₂₂H₂₉N₃O₄S.CH₃SO₃H.0.2H₂O.

EXAMPLE 3ww2-(3-Indolyl)-N-methyl-N-[(1S)-1-phenyl-2-[(3S)-1-pyrrolidin-3-ol]ethyl]-acetamidehydrochloride

Compound 3ww was prepared from indole-3-acetic acid (477 mg; 2.72 mmol),DCC (1.12 g; 5.44 mmol), pyridine (0.440 mL; 5.44 mmol) andS-(−)-3-pyrrolidinol (600 mg; 2.72 mmol, for preparation see EP 0398 720A2) in 15 mL of dry methylene chloride. After stirring at roomtemperature for 24 h, TLC (95:5 methylene chloride:methanol w/2%ammonia) indicated the reaction was complete. The reaction was quenchedwith sat. sodium bicarbonate and the layers were separated. The organiclayer was washed with brine, dried over anhydrous sodium Sulfate,filtered and conc. in vacuo to give 2.04 g of a viscous yellow oil whichwas purified by flash chromatography using a stepwise gradient of 2% to3% methanol:methylene chloride with 2% ammonia to yield 700 mg (69%) ofdesired compound which was converted to the hydrochloride salt withHCl/ether to give 720 mg of 3ww. m.p. 142° C.(dec.); ¹H NMR (HCl salt,CDCl₃, 300 MHz) δ2.1 (br, m 4H), 2.8 (s, 3H), 4.5 (m, 1H), 6.3 (br, m,1H), 7.2 (br, m, 1H), 7.3 (complex, 4H, aromatic), 7.5-7.6 (d, 2H), 7.8(d, 2H). Fab MS (MH⁺): 377. Anal. Calcd for C₂₃H₂₇O₂N₃.HCl: C, 63.29; H,7.04; N, 9.63. Found C, 63.15; H, 7.03; N, 9.57.

EXAMPLE 3xx2-(2-N-Benzyl-2-N-methylsulfamoyl-3,4-dimethoxyphenyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamidehydrochloride

Compound B was prepared from methyl 3,4-dimethoxyphenyl acetatefollowing the literature procedure[J. Het. Chem. 29, 1667 (1992)] andcondensed with the diamine in usual fashion to give 3xx in 60% yield; mp188-190° C.; ¹H NMR (300 MHz, CDCl₃) δ1.88 (m, 4H), 2.64 (s, 3H),2.85-3.25 (m, 4H), 2.91 (s, 3H), 3.90 (s, 3H), 3.94-4.28 (m, 2H), 3.95(s, 3H), 4.30-4.60 (m, 4H), 6.48 (m, 1H), 7.15-7.40 (m, 11H), 7.55 (s,1H). Anal. Calcd. for C₃₁H₃₉N₃O₅S.HCl.0.5H₂O: C, 60.92; H, 6.76; N,6.88. Found: C, 60.73; H, 6.99; N, 6.82.

EXAMPLE 3yy2-(N-Methylsulfonamido-2-aminophenyl)-N-methyl-N-[(1R)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamidemethane sulfonate

Compound 3yy was prepared using the same synthetic scheme as describedin U.S. Pat. No. 5,688,955 using(R)-1-[2-methylamino-2phenyl)ethyl]pyyrolidine(for preparation see J.Med. Chem. 34, 1991 pp181, Costello, G. F. et. al m.p. 179-181° C.: ¹HNMR (Mesylate salt, CDCl₃, 300 MHz) δ2.0-2.2 (br, m, 4H), 2.8 (s, 3H),3.0 (s, 3H), 3.6 (d, 2H), 6.2-6.3 (d, 1H), 7.1 (m, 3H), 7.2 (m, 1H), 7.3(m, 3H), 7.7 (d, 2H). Fab MS (MH⁺): 415. Anal. Calcd. for C₂₃H₃₃O₆N₃S₂:C, 53.99; H, 6.50; N, 8.21. Found C, 53.98; H, 6.41; N, 8.10.

EXAMPLE 3zz(R,S)-1-(4-Trifluoromethylphenyl-N-methylacetamido)-1-(3-methoxyphenyl)-2-(1-pyrrolidino)-ethane,methanesulfonic acid salt

The procedure is the same as that of 3uu. Yield: 74%. Mp.: 166-168° C.NMR (CDCl₃), δ (ppm): 2.11 (2H, m), 2,16-2.32 (2H, m), 2.81 (3H, s),2.85-2.98 (4H, m), 3.12-3.21 (1H, m), 3.75 (3H, s), 3.83 (1H, m),4.05-4.33 (4H, m), 6.30 (1H, dd, J=2.6, 12.0 Hz), 6.67 (1H, d, J=1.8Hz), 6.75 (1H, d, J=7.6 Hz), 6.87 (1H, dd, J=2.4, 8.3 Hz), 7.30 (1H, m),7.45 (1H, d, J=8.1 Hz), 7.57 (1H, d, J=8.1 Hz). MS (FAB) m/z 421. Anal.(C, H, N) C₂₃H₂₇N₂O₂F₃.CH₃SO₃H.

EXAMPLE 3aaa(R,S)-1-(4-Trifluoromethylphenyl-N-methylacetamido)-1-(3-hydroxyphenyl)-2-(1pyrrolidino)-ethane,methanesulfonic acid salt

The procedure is the same as that of 3vv. Yield: 38.5%. Mp: 158-160° C.NMR (CDCl₃), δ (ppm): 2,01-2.14 (4H, m), 2.73 (3H, s), 2.82 (3H, s),2.94 (2H, m), 3.30 (1H, m), 3.76 (1H, m), 4.03-4.14 (4H, m), 6.20 (1H,dd, J=3.3, 11.0 Hz), 6.63 (1H, d, J=7.9 Hz), 6.86 (1H, dd, J=1.8, 8.0Hz), 7.06 (1H, s), 7.18 (1H, t, J=8.0 Hz), 7.41 (2H, d, J=8.0 Hz), 7.56(2H, d, J=8.0 Hz).). MS (FAB) m/z 407. Anal. (C, H, N)C₂₂H₂₅N₂O₂F₃.1.1CH₃SO₃H.

EXAMPLE 3bbb

2-Fluorophenyl-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]-acetamidehydrochloride

Compound 3bbb was prepared using the same general EDCI/DIPEA couplingprocedure as described in U.S. Pat. No. 5,688,955 with2-fluorophenylacetic acid (415 mg; 2.69 mmol), HOBT(363 mg; 2.69 mmol),EDCI (514 mg; 2.69 mmol),N,N-diisopropylethylamine(0.63 mL; 3.66 mmol),and (1S)1-[(2-methylamino-2-phenyl)ethyl]pyrrolidine(500 mg; 2.44 mmol)in 10 mL of dry methylene chloride at room temperature. After 24 h,TLC(95:5 methylene chloride:methanol w/2% ammonia) indicated thereaction was complete. The reaction solution was quenched with sat.sodium bicarbonate and the layers were separated. The organic layer waswashed with brine, dried over anh. sodium sulfate, filtered and conc. invacuo to give 900 mg of a dark brown oil which was purified by flashchromatography using a stepwise gradient of 2% to 4% methanol:methylenechloride with 2% ammonia to yield 750 mg(90%) of desired product whichwas converted to the hydrochloride salt with HCl/ether to give 880 mg of3bbb. m.p. 255° C.(dec.); ¹H NMR (HCl salt, CDCl₃, 300 MHz) δ2.0 (br,m,4H), 2.1-2.2 (br, m, 2H), 2.9 (s, 3H), 3.8-4.0 (dd, 4H), 7.0-7.4(complex, 9H, aromatic). Fab MS (MH⁺): 340. Anal. Calcd. forC₂₁H₂₅ON₂F.HCl : C, 66.97; H, 6.95; N, 7.43. Found C, 66.76; H, 6.90; N,7.43.

EXAMPLE 3ccc4-Fluorophenyl-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamidehydrochloride (3ccc)

Compound 3ccc was prepared using the same general EDCI/DIPEA couplingprocedure from U.S. Pat. No. 5,688,955 with 4-fluorophenylacetic acid(415 mg; 2.69 mmol), HOBT (363 mg; 2.69 mmol), EDCI (514 mg; 2.69 mmol),N,N-diisopropylethylamine (0.63 mL; 3.66 mmol) and(1S)1-[(2-methylamino-2-phenyl)ethyl]pyrrolidine (500 mg; 2.44 mmol) in10 mL of dry methylene chloride at room temperature. After 24 h,TLC(95:5 methylene chloride:methanol w/2% ammonia) indicated thereaction was complete. The reaction was quenched with sat. sodiumbicarbonate and the layers were separated. The organic layer was washedwith brine, dried over anh. sodium sulfite, filtered and conc. in vacuoto give 900 mg of a dark brown oil which was purified by flashchromatography using a stepwise gradient of 2% to 3% methanol:methylenechloride with 2% ammonia to yield 800 mg (96%) of desired product whichwas converted to the hydrochloride salt with HCl in ether to give 3ccc.m.p.>260° C.(dec.); ¹H NMR (HCl salt; CDCl₃, 300 MHz) δ2.0 (br, m, 4H),2.1-2.2 (br, m, 2H), 2.9 (s, 3H), 3.8-4.0 (dd, 4H), 7.0-7.4 (complex,9H, aromatic). Fab MS (MH⁺): 340. Anal Calcd for C₂₁H₂₅ON₂.HCl: C,66.82; H, 6.95; N, 7.43. Found C, 66.81; H, 6.94; N, 7.48

EXAMPLE 3ddd(E)-4-[2-(2-Amino-4,5-dichlorophenyl)-N-methyl-N-[(1S)-1-phenyl)-2-[1-pyrrolidinyl]ethyl]acetamido]4-oxo-2-butenoicacid hydrochloride

To a solution of 3y (1.4 g, 2.63 mmol) in THF:CH₃OH (1:1, 20 mL) at roomtemperature was added 1M LiOH aqueous solution (5.3 mL, 5.26 mmol) andthe reaction mixture was stirred for 8 h. Progress of reaction wasfollowed by TLC and reaction mixture was acidified to pH 4.0 from 1NHCl. The solvent was removed under reduced pressure. The residue wastriturated with CH₂Cl₂ (3×45 mL). The combined organic layer was washedwith sat. salt solution which resulted in the precipitation of thecompound. The solid was filtered off, washed with a smmal amount ofwater, anhydrous ether, and dried to give 3ddd 0, 0.85 g (59%); mp205-207° C. (d); ¹H NMR (300 MHz, DMSO-d₆) δ1.93 (m, 4H), 2.84 (s, 3H),3.00-3.75 (m, 6H), 3.98 (d, J=15.0 Hz, 1H), 4.05 (m, 1H), 4.35 (d,J=16.5 Hz, 1H), 6.12 (m, 1H), 6.65 (d, J=15.4 Hz, 1H), 7.25-7.38 (m, 5H), 7.55 (s, 1H), 7.79 (d, J=15.0 Hz), 1H), 8.31 (s, 1H). Anal Calcd.for C₂₅H₂₇Cl₂N₃O₄.HCl.NaCl.1.5H₂O: C, 47.94; H, 4.99; N, 6.71. Found: C,47.98; H, 4.92; N, 6.57.

Compounds of Formula IV Intermediates

The following intermediates were prepared.

Synthesis of Diamine 3

(±)-trans-2-Pyrrolidinyl-N-methylcyclohexylamine (3)

The racemic diamine (3) was prepared by a number of procedure reportedin the literature.^(10,11) Alternatively, the amine was also preparedfrom cyclohexene oxide (1) following the procedure described in Scheme Iand the literature¹² in 70% overall yield as brown oil. A sample waspurified by the distillation (b.p. 75-82° C./1.0 mm, lit.² b.p. 76-80°C./1.2 mm); ¹H-NMR (200 MHz, CDCl₃) δ1.04-1.36 (m, 4H), 1.49-1.89 (m,8H), 2.18 (d, J=5.0 Hz,1H), 2.52 (s, 3H), 2.56-2.70 (m, 4H), 2.80-2.93(m, 1H), 7.75 (bs, 1H). The corresponding chiral amine (3) could beprepared following the literature procedures.

Ref.

(10) Szmwuszkovicz, J.; Von Voigtlander, P. F. J. Med. Chem. 1982, 25,1125-1126.

(11) DeCosata, B.; George, C.; Rothman, R. B.; Jacobson, A. E.; Rice, K.E. FEBBS Lett. 1987, 223, 335-339.

(12) Freeman, J. P.; Michalson E. T.; D'Andrea, S. V.; Bacynskyj, L.;Von Voigtlander, P. F.; Lahti, R. A.; Smith, M. W.; Lawson, C. F.;Scahill, T. A.; Mizsak, S. A.; Szmuszkovicz, J. J. Med. Chem. 1991, 34,1891-1896.

Synthesis of Arylacetamides

General Procedure for the Preparation of aryl acetamides (±) HCl

To a stirred solution of aryl acetic acid (4) (1.5 mmol) in 20 mL of dryCH₂Cl₂ was added pyridine (0.5 mmol) at 0→5° C. under a nitrogenatmosphere. N,N′-Dicyclohexyl-carbodiimide (2.0 mmol) was added in oneportion and the reaction mixture was continued stirring for 30 min whilewarming to room temperature. A solution of the (±) 3 (1.0 mmol) in 10 mLof dry CH₂Cl₂ was added and the progress of the reaction was monitoredby TLC in solvent system corresponds to CHCl₃:CH₃OH:28% NH₄OH (93:5:2).After disappearance of the diamine 3, the reaction mixture was quenchedwith saturated NaHCO3 and stirring was continued for addition 15 mm. Theprecipitated N,N′-dicyclohexylurea (DCU) was removed by filtration andthe filter cake was washed with additional amounts of CH₂Cl₂. Thecombined filtrate was evaporated to dryness and the residue was purifiedeither on a silica gel column or using Chroatotran silica gel plattesform the from the solvent system mentioned for each compound to give (±)5 as free base. The hydrochloride salts were prepared from dissolving(±) 5 in minimum amount of CH₂Cl₂ and addition of 2.0 equivalents of 1Metherial HCl. The solvents were removed under reduced pressure and theHCl salts were recystallized from the solvents indicated below. Theyields given below are for overall steps.

EXAMPLE 103(±)-trans-2-Nitro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]phenylacetamideHydrochloride [(±) 5a HCl] ADL-0.1-0012-3

Prepared from 2-nitrophenylacetic acid [solvent forpurification-CH₂Cl₂:CH₃OH:28%NH₄OH (98:2:2)]: yield 21% as a white solid(2-prppanol); mp 267-269° C. (d); ¹H NMR((200 MHz, CDCl₃) δ1.00-1.44 (m,2H), 1.60-2.35 (m, 8H), 2.85 (m, 1H), 3.15 (s, 3H), 3.18-3.35 (m, 4H),3.40 (m, 1H), 3.85 (m, 1H), 4.33 (dd, J=10.0 Hz, 2H), 4.64 (m, 1H), 7.35(m, 1H), 7.56 (m, 2H), 8.05 (d, J=7.8 Hz, 1H), 11.02 (bs, 1H). Anal.Calcd for C₁₉H₂₇N₃O₃.HCl: C, 59.75; H, 7.39; Cl, 9.28; N, 11.00. Found:C, 59.98; H, 7.38; 8.96; N, 10.85.

EXAMPLE 104(±)-trans-2-Amino-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]phenylacetamideHydrochloride [(±) 5b HCl] ADL-01-0014-9

To a solution of (±) 5a HCl (0.5 g, 1.31 nmol) in 30 mL of CH₃OH wasadded 10% Pd/C (100 mg) and hydrogenated at 50 PSI in a Parr Apparatusat ambient temperature for 3 h. The catalyst was removed by filtrationthrough a celite pad and washed with hot CH₃OH and the combined filtratewas evaporated to dryness. The residue was recrystallized from2-propanol to give (±) 5b HCl as a white solid, 0.45 g (95%); mp213-215° C.; ¹H NMR(200 MHz, CDCl₃) δ1.05-1.40 (m, 2H), 1.65-2.25 (m,8H), 3.10 (s, 3H), 2.90-3.25 (m, 4H), 3.50 (d, J=12.0, 1H), 3.65 (m,1H), 3.88 (m, 1H), 4.20 (d, J=12.5 Hz, 1H), 4.70 (m, 1H), 6.65 (m, 2H),7.00 (m, 2H), 7.25 (bs, 2H). Anal. Calcd for C₁₉H₂₉N₃O.HCl.0.5H₂O: C,63.23; H, 8.66; N, 11.64. Found: C, 63.59; H, 8.76; N, 11.61.

EXAMPLE 105(±)-trans-2-Nitro-4,5-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-phenylacetamideHydrochloride [(±) 5c HCl] ADL-01-0015-6

The compound was prepared according to the literature method (DeCosata,B.; Linda, B.; Rothman, R. B.; Jacobson, A. E.; Bykov, V.; Pert, A.;Rice, K. E. FEBBS Lett. 1989, 249, 178-182); ¹H NMR(200 MHz, CDCl₃)δ1.15-1.45 (m, 2H), 1.55-2.30 (m, 8H), 3.10 (s, 3H), 2.85-3.20 (m, 4H),3.40 (m 1H), 3.88 (m, 1H), 4.25 (d, J=14.5 Hz, 1H), 4.45 (d, J=15.0 Hz,1H), 4.65 (m, 1H), 7.70 (s, 1H), 8.13 (s, 1H). Anal. Calcd forC₁₉H₂₅Cl₂N₃O₃.HCl: C, 50.62; H, 5.81; N, 9.32. Found: C, 50.61; H, 5.61;N, 9.20.

EXAMPLE 106(±)-trans-2-Amino-4,5-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]phenylacetamideHydrochloride [(±) 5d HCl] ADL-01-0016-4

Obtained from (±) 5c HCl following the literature procedure (DeCosata,B.; Linda, B.; Rothman, R. B.; Jacobson, A. E.; Bykov, V.; Pert, A.;Rice, K. E. FEBBS Lett. 1989, 249, 178-182); ¹H NMR(200 MHz, CDCl₃)δ1.10-1.40 (m, 4H), 1.48-2.20 (m, 8H), 3.00 (s, 3H), 3.10-3.30 (m, 4H),3.55 (d, J=14.0 Hz, 1H), 3.85 (d, J=14.0 Hz, 1H), 4.50 (m, 1H), 6.75 (s,1H), 7.08 (s, 1H). Anal. Calcd for C₁₉H₂₇Cl₂N₃O.HCl0.75H₂O: C, 52.54; H,6.84; N, 9.67. Found: C, 52.561; H, 6.63; N, 9.33.

EXAMPLE 107(±)-trans-2-Methanesulfonamido-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-phenylacetamideHydrochloride [(±) 5e HCl] ADL-01-0025-5

To a solution of free base of (±) 5b (1.0 g, 3.2 mmol) in 40 mL of dryCH₂Cl₂ at 0° C. under a nitrogen atmosphere was added Et₃N (1.86 g, 18.4mmol). A solution of methanesulfonyl chloride (1.14 g, 9.92 mmol) in 15mL of dry CH₂Cl₂ was added dropwise within 15 min. After 2 h at roomtemperature TLC [solvent system: CHCl₃:CH₃OH:28% NH₄OH (93:5:2)] showedstill staring material was present. Additional amounts of Et₃N(1.86 g)and methanesulfonyl chloride (1.14 g) were added and stirring wascontinued for another 2 h by this time no starting material was presentin the reaction mixture. After the mixture was diluted with 40 mL CH₂Cl₂of, it was washed with saturated NaHCO₃, water, saturated salt solution,and dried over anhydrous Na₂SO₄. Removal of solvent under reducedpressure gave the bis-sulfoamide as a brown foam which was used directlyin the following hydrolysis.

To a solution of bis-sulfonamide (1.0 g, 2.12 mmol) in 60 mL ofCH₃OH:THF (2:1) was added 10 M aqueous NaOH (0.96 mL, 9.6 mmol).¹³ Themixture was stirred at room temperature for 30 min and then acidifiedwith 1N HCl. The solvent was evaporated under reduced pressure and theresidue was redissolved in CH₂Cl₂. The CH₂Cl₂ layer was then washed with5% NaHCO₃, saturated salt solution, and dried over anhydrous Na₂SO₄.Removal of solvent under reduced pressure chromatography on a silica gelcolumn [solvent system: CH₂Cl₂:CH₃OH:28% NH₄OH (95:5:2)] gave themono-sulfonamide (free base) as an oil; ¹H NMR (200 MHz, CDCl₃)δ1.05-1.95 (m, 12H), 2.45-2.80 (m,5H), 2.95 (s, 3H), 3.10 (s, 3H), 3,50(d, J=13.8 Hz, 1H), 3.65 (m, 1H), 3.85 (d, J=14.0 Hz, 1H), 4.45 (m, 1H),7.05 (m, 1H), 7.15 (m, 2H), 7.45 (d, J=8.5 Hz, 1H). The hydrochloridesalt was prepared by dissolving the free base in CH₂Cl₂ and adding 1.2equivalents of 1M etherial HCl and recrytallizing from 2-propanol togive (±) 5e HCl as beige colored solid, 0.37 g (38%); mp 229-231° C.; ¹HNMR (200 MHz, CDCl₃) δ1.10-2.20 (m, 12H), 2.90-3.20 (m, 4H), 3.00 (s,3H), 3.15 (s, 3H), 3.50 (m, 1H), 3.65 (d, J=13.5 Hz, 2H), 3.80 (m, 1H),4.40 (m, 1H), 7.05-7.30 (m, 3H), 7.60 (d, J=8.0 Hz, 1H), 8.90 (bs, 1H).Anal. Calcd for C₂₀H₃₁N₃O₃S.HCl.0.25H₂O: C, 55.28; H, 7.54; N, 9.67.Found: C, 55.40; H, 7.39; N, 9.49.

Ref.

(13) Li, C.-S.; Black, W. C.; Chan, C.-C.; Ford-Huctchinson, A. W.;Gauthier, J.-Y.; Gordon, R.; Guay, D; Kargman S.; Lau, C. K; Mancini,J.; Ouimet, N.; Roy, P.; Vickers, P.; Wong. E.; Young, R. N.; Zamboni,R.; Prasit, P. J. Med. Chem. 1995, 38, 4897-4905.

EXAMPLE 108N-[2-(±)-trans-N-Methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-phenylacetamido]glycineHydrochloride [(±) 5f HCl] ADL-01-0028-9

To a stirred solution of (±) 5b (free base, 1.0 g, 3.2 mmol) in 15 mL ofdry DMF at room temperature under a nitrogen atmosphere was added 95%NaH (0.083 g, 3.3 mmol). After stirring at room temperature for 30 min,the turbid solution was added to a stirred solution of tert-butylbromoacetate (0.66 g, 3.4 mmol) in 10 mL of dry DMF. The reactionmixture was continued stirring for 72 h however TLC of the reactionmixture (solvent system: CHCl₃:CH₃OH:28% NH₄OH (93:5:2)] showed stillstarting material was present. The solvent was removed under reducedpressure and the residue was partioned between CH₂Cl_(2/)water. Theproduct was purified on a silica gel column from CH₂Cl₂:CH₃OH (9:1) andwas recystallized from CH₂Cl₂:Et₂O (1:1) to give the correspondingtert-butyl ester, 0.16 (12%); ¹H NMR (200 MHz, CDCl₃) δ1.05-1.35 (m,4H), 1.35 (s, 9H), 1.55-2.20 (m, 8H), 2.92 (b, 4H), 3.12 (s, 3H), 3.45(m, 1H), 3.60 (d, J=14.0 Hz, 2H), 3.78 (bt, 2H), 3.95 (m, 1H), 5.75 (b,1H),6.38 (d, J=6.5 Hz, 1H), 6.60 (t, J 5.5 Hz, 1H), 7.00 (m, 2H). Thestarting material was also recovered in 50% yield.

The tert-butyl ester (0.16 g, 0.372 mmol) was suspended in 10 mL of 4Naqueous HCl and added one drop of anisole and the mixture was stirred atroom temperature for 24 h. The solvent was evaporated under reducedpressure and the residue was redissolved in CH₃CN and filtered. Thefiltrate was evaporated under reduced pressure and the residue wasrecrystallized from 2-propanol:ether (1:1) to give (±) 5f HCl as a whitesolid, 0.070 g (42%); mp 212-214° C. (d); ¹H NMR (200 MHz, DMSO-d₆)δ1.15-2.25 (m, 12H), 2.90 (m, 1H), 3.05 (s, 3H), 3.14-3.70 (m, 6H), 3.85(bs, 2H), 4.55 (b, 1H), 6.37 (d, J=6.0 Hz, 1H), 6.55 (t, J=5.0 Hz, 1H),6.95 (m, 2H), 9.80 (b, 1H). Anal. Calcd for C₂₁H₃₁N₃O₃.HCl.H₂O: C,58.93; H, 8.00; N, 9.81. Found: C, 58.79; H, 7.64; N, 9.43.

EXAMPLE 109(±)-trans-4-Trifluoromethyl-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-phenylacetamideHydrochloride [(±) 5g HCl] ADL-01-0066-9

To a solution of 4-trifluoromethylphenyl acetic acid (1.45 g, 7.08 mmol)in 10 mL of dry CH₂Cl₂ under a nitrogen atmosphere was added1-hydroxybenzotriazole hydrate (HOBT) (0.95 g, 7.08 mmol) and stirred.The reaction mixture was cooled to 0→5° C. and added solid EDCI([1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide HCl])(1.35 g, 7.08mmol) and stirrat this temperature for 30 min. A solution (±) 3 (1.0 g,5.48 mmol) in 10 mL of dry CH₂Cl₂ was added followed byN,N-diisopropylethylamine (Hunig's Base) (0.915 g, 7.08 mmol). Thereaction mixture was stirred for 24 h while warming to the roomtemperature. The reaction mixture was then poured on to excess ofice-cold saturated aqueous NaHCO3 solution and stirred for 30 min. Afterdilution with CH₂Cl₂, the organic was separated washed with saturatedsalt solution, and dried over anhydrous Na₂SO₄. Removal of solvent gavea brown oil which was chromatogrphed on a silica gel column [solventsystem: CH₂Cl₂:CH₃OH:28% NH₄OH (99:1:2)] to give the desired product asfree base. The hydrochloride salt was prepared from 1M etherial HCl andrecrystallized from CH₂Cl₂:Et₂O (1:1) to give (±) 5g HCl as a creamcolored solid, 0.68 g (30%4); 213-215° C.; ¹H NMR (200 MHz, CDCl₃)δ1.02-1.47 (m, 4H), 1.52-2.22 (m, 8H), 2.75-2.90 (m, 2H), 2.94 (s, 3H),3.07 (m, 1H), 3.37 (m, 1H), 3.62 (d, J=15.0 Hz, 1H), 3.77 (m, 1H), 4.17(d, J=15.0 Hz, 1H), 4.57 (m, 1H), 7.30 (d, J=8.0 Hz, 2H), 7.38 (d, J=8.0Hz, 2H). Anal. Calcd for C₂₀H₂₇F₃N₂O.HCl.0.25H₂O: C, 58.68; H, 7.02; N,6.84. Found: C, 58.68; H, 6.84; N, 6.69.

Nitration of 4-trifluorometylphenyl acetic acid General Procedure

Preparation of 2-nitro-4-trifluoromethylphenyl acetic acid[4,R=2-NO₂(4-CF₃)—C₆H₄CH₂]

To a solution of 4-trifluoromethylphenyl acetic acid (2.5 g, 12.25 mmol)in 8 mL of glacial acetic acid at 0° C. under an anhydrous atmospherewas added 5 mL of fuming H₂SO₄ (11% SO₃) (caution!) followed by cautiousaddition of 90% HNO₃ (3.5 mL, 73.14 mmol) within 10 min. The reactionmixture was then stirred at room temperature for 2 h and poured intoice-water. The resulting solid was filtered and washed with colddeionized water to give the desired product after drying as off-whitesolid, 2.5 g (82%); ¹H NMR (200 MHz, CDCl₃) δ4.02 (s, 2H), 7.41 (d,J=8.0 Hz, 2H), 7.74 (d, J=8.0 Hz, 2H), 8.28 (s, 1H). The product wasused directly into the following reactions.

EXAMPLE 110(±)-trans-2-Nitro-4-trifluoromethyl-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-phenylacetamideHydrochloride [(±) 5h HCl] ADL-01-0065-1

Prepared from 2-nitro-4-trifluoromethylphenyl acetic acid following theprocedure described in Example II to give (±) 5h HCl as cream coloredsolid in 56% yield; mp 259-261° C. (d); ¹H NMR (200 MHz CDCl₃)δ1.10-1.42 (m, 4H), 1.51-2.25 (m, 8H), 2.95-3.25 (m, 3H), 3.14 (s, 3H),3.40 (m, 1H), 3.90 (m, 1H), 4.35 (d, J=13.8 Hz, 1H), 4.55 (d, J=14.0 Hz,1H), 4.60 (m, 1H), 7.80 (dd, J=7.8 Hz, 2H), 8.25 (s, 1H). Anal. Calcdfor C₂₀H₂₆F₃N₃O₃.HCl.0.25H₂O: C, 52.86; H, 6.10; N, 9.25. Found: C,52.85; H, 6.02; N, 9.13.

EXAMPLE 111(±)-trans-2-Amino-4-trifluoromethyl-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-phenylacetamideHydrochloride [(±) 5i HCl] ADL-01-0080-0

To a solution of free base 4h (0.4 g, 0.97 mmol) in 20 mL of absolutealcohol was added 2 ml of hydrazine hydrate and the reaction mixture wasstirred at 50° C. under a nitrogen atmosphere. Raney®nickel (50% slurryin water) was added slowly and the progress of the reaction wasmonitored on TLC plate [solvent system: CHCl₃:CH₃OH:28% NH4OH (99:1:2)].If needed more of the Raney®nickel was added to the reaction mixture.When reaction was completed, excess of Raney®nickel was introduced todecompose the hydrazine hydrate. The reaction mixture was filteredthrough a celite pad and the pad was washed with hot CH₃OH. The filtratewas evaporated to dryness. The residue was purified on a silica gelcolumn [solvent system: CHCl₃:CH₃OH:28% NH₄OH (99:1:2)] and thehydrochloride salt was prepared from 1M etherial HCl. Recrystallizationfrom CH₂Cl₂:Et₂O (2:1) gave (±) 5i HCl as a white solid, 0.2 g (48%); mp248-250° C. (d); ¹H NMR (200 MHz, DMSO-d₆) δ1.15-2.18 (m, 12H), 3.00 (s,3H), 3.15-4.10 (m, 7H), 4.50 (m, 1H), 6.80(d, J=7.8 Hz, 1H), 6.92 (s,1H), 7.10 (d, J=8.0 Hz, 1H), 10.0 (bs, 1H). Anal. Calcd forC₂₀H₂₈F₃N₃O.HCl.0.5H₂O: C, 56.01; H, 7.05; N, 9.80. Found: C, 55.70; H,7.03; N, 9.65.

EXAMPLE 112(±)-trans-2-Bismethanesulfonamido-4-trifluoromethyl-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-phenylacetamideHydrochloride [(±) 5j HCl] ADL-01-0118-8

The compound was prepared from free base (±) 5i (0.5 g, 1.30 mmol)following the procedure described in the first part of the preparationof (±) 5e. The bismethaneslfonamide was purified on a silica gel column[solvent system: CH₂Cl₂:CH₃OH:28% NH₄OH (96:2:2)] to give the desiredproduct as a foam. The hydrochloride salt was prepared from 1M etheialHCl and recrystallized from 2-propanol:Et₂O (1:1) to give (±) 5j HCl asa beige colored solid, 0.23 g (30%); mp 224-226° C. (d); ¹H NMR (200MHz, CDCl₃) δ1.12-1.51 (m, 4H), 1.53-2.24 (m, 8H), 1.82-3.17 (m, 2H),2.98 (s, 3H), 3.32-3.56 (m, 2H), 3.28 (s, 3H), 3.33 (s, 3H), 3.77 (m,1H), 3.97 (d, J=14.0 Hz, 1H), 4.27 (d, J=14.0 Hz, 1H), 4.62 (m, 1H),7.39 (s, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.85 (d, J=8.0 Hz, 1H). Anal.Calcd for C₂₂H₃₂F₃N₃O₅S₂.HCl: C, 45.87; H, 5.77; N, 7.29. Found: C,45.53; H, 5.81; N, 7.00.

EXAMPLE 113(±)-trans-2-Methanesulfonamido-4-trifluoromethyl-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-phenylacetamideHydrohloride [(±) 5k HCl] ADL-01-0137-8

To a solution of (±) 5j HCl (0.16 g, 0.23 mmol) in 9 mL of CH₃OH:THF(2:1) at room temperature was added 0.12 mL of 10M aqueous NaOH and themixture was stirred for 30 min. The reaction mixture was neutralizedwith 1N HCl and evaporated to dryness. The residue was redissolved inCH₂Cl₂ and basified with saturated aqueous solution of NaHCO₃. Theorganic layer was separated, washed with water, saturated salt solution,and dried over anhydrous Na₂SO₄. Removal of solvent under reducedpressure gave the product as a free base. The hydrochloride salt wasprepared from 1M etherial HCl and recrystallized from CH₂Cl₂:Et₂O (1:1)to give (±) 5k HCl as a beige colored solid, 0.085 g (61%); 209-211° C.(d); ¹H NMR (200 MHz, CDCl₃) δ1.15-1.24 (m, 4H), 1.50-2.10 (m, 8H), 2.20(m, 2H), 2.90-3.10 (m, 2H), 3.05 (s, 6H), 3.55 (m, 2H), 3.80 (m, 1H),4.64 (m, 1H), 7.20 (dd, J=7.8 Hz, 2H), 7.88 (s, 1H), 9.00 (s, 1H). Anal.Calcd for C₂₁H₃₀F₃N₃O₃S.HCl.0.125H₂O: C, 50.42; H, 6.30; N, 8.40. Found:C, 50.62; H, 6.49; N, 8.00.

EXAMPLE 114N-[2-(±)-trans-4-Trifluoromethyl-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-phenylacetamido]glycineHydrochloride [(±) 5l HCl] ADL-01-0130-3

To a solution of free base (±) 5i (0.767, 2.0 mmol) in 10 mL ofanhydrous THF under a nitrogen atmosphere at 0° C. was addedN,N-diisopropylethylamine (Hunig's Base) (1.55 g, 12.0 mmol). Thereaction mixture was stirred at 0° C. for 15 min then added bromoaceticacid t-butyl ester (1.95 g, 10.0 mmol) and the reaction mixture wascontinued to stir while warming to room temperature 72 h. The solventwas evaporated at reduced pressure and the residue was partitionedbetween CH₂Cl₂ and water. The organic layer was then washed with,saturated NaHCO₃, saturated salt solution, and dried over anhydrousNa₂SO₄.Removal of solvent gave the crude product which was purified on asilica gel column [solvent system: CHCl₃:CH₃OH:28% NH₄OH (96:2:2)] togive the intermediate t-butyl ester 0.477 g (40%); ¹H NMR (200 MHz,CDCl₃) δ1.05-1.25 (m, 4H), 1.38-1.90 (m, 8H), 1.40 (s, 9H), 2.15-2.75(m, 5H), 2.85 (s, 3H), 3.60 (m, 2H), 3.75 (d, J=4.0 Hz, 2H), 4.45 (m,1H), 5.85 (m, 1H), 6.55 (s, 1H), 6.80 (d, J=7.5 Hz, 1H), 7.10 (d, J=7.8Hz, 1H).

The above t-butyl ester (0.47 g, 0.77 mmol) was suspended in 10 mL ofaqueous 4N HCl and added 2-3 drops of anisole. The reaction mixture wasstirred at room temperature for 72 h and filtered. The filtrate wasevaporated to dryness, redissolved in CH₃CN, filtered again, andconcentrated. Addition of the ether gave the product which was filtered,washed with ether, and dried to give (±) 5l HCl as a beige coloredsolid, 0.17 g (41%); mp 178-180° C. (d); MS (FAB) 442 (M+1); ¹H NMR (200MHz, CDCl₃) δ1.05-2.20 (m, 12H), 2.75 (s, 3H), 2.90-3.25 (m, 5H),3.30-3.55 (m, 2H), 3.70-4.35(m, 4H), 4.65 (m, 1H), 6.72 (s, 1H), 6.80(m, 1H), 6.95 (d, J=7.7 Hz, 1H). Anal. Calcd forC₂₂H₃₀F₃N₃O₃.HCl.0.125Et₂O: C, 55.47; H, 6.67; N, 8.62. Found: C, 55.64;H, 7.06; N, 9.00.

EXAMPLE 115(±)-trans-3-Trifluoromethyl-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-phenylacetamideHydrochloride [(±) 5m HCl] ADL-01-0083-4

Following the Example II, (±) 5m HCl was prepared from3-trifluoromethylphenyl acetic acid in 67% yield as a cream coloredsolid; mp 245-247° C.; ¹H NMR (200 MHz, CDCl₃) δ1.15-1.55 (m, 4H),1.60-2.30 (m, 8H), 2.80-3.05 (m, 2H), 3.00 (s, 3H), 3.18 (m, 1H), 3.45(m, 1H), 3.75 (d, J=15.0 Hz, 1H), 3.85 (m, 1H), 4.25 (d, J=14.8 Hz, 1H),4.65 (m, 1H), 7.40 (m, 4H). Anal. Calcd for C₂₀H₂₇F₃N₂O.HCl.0.25H₂O: C,58.68; H, 7.02; N, 6.84. Found: C, 58.46; H, 7.17; N, 6.69.

Nitration of 3-trifluorometylphenyl acetic acid

Preparation of 2-nitro-3-trifluoromethylphenyl acetic acid[4,R=2-NO₂(3-CF₃)—C₆H₄CH₂] and preparation of5-nitro-3-trifluoromethylphenyl acetic acid [4,R=5-NO₂(3-CF₃—C₆H₄CH₂]

The nitration of 3-trifluorophenylacetic acid as shown earlier resultedinto a 1:1 non-separable mixture of 2- and 5-nitro compounds in 66%yield. The structural assignment of the compounds were made on the basisof ¹H NMR spectrum. The mixture was used in the condensation reaction.

EXAMPLE 116(±)-trans-5-Nitro-3-trifluoromethyl-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-phenylacetamideHydrochloride [(±) 5n HCl] and(±)-trans-2-Nitro-3-trifluoromethyl-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-phenylacetamideHydrochloride [(±) 5o HCl] ADL-01-0087-5 and ADL-01-0088-3

The compounds were prepared as shown in Example 109 and the mixture of2-and 5-nitrophenylacetic acids to give the mixture of products.Initially the compounds were separated on a silica gel column [solventsystem: CHCl₃:CH₃OH:28% NH₄OH (96:2:2)] which resulted in the free baseof the compounds as pure mixture. The products were again purified onChromatotran using a 4 mm silica gel plate [solvent system: CHCl₃containing 2% NH₄OH]. The first product was isolated and converted tothe hydrochloride salt and the salt was recrystallized from2-propanol:ether (1:1) to give (±) 5n HCl as a cream colored solid in10% yield; mp 236-238° C.; ¹H NMR (200 MHz, CDCl₃) δ1.15-1.55 (m, 4H),1.65-2.30 (m, 8H), 2.85-3.20 (m, 3H), 3.10 (s, 3H), 3.40 (m, 1H), 3.70(d, J=14.0 Hz, 1H), 3.85 (m, 1H), 4.60 (brd, 2H), 7.90 (s, 1H), 8.25 (s,1H), 8.32 (s, 1H). Anal. Calcd for C₂₀H₂₆F₃N₃O₃.HCl: C, 53.39; H, 6.05;N, 9.34. Found: C, 53.28; H, 6.06; N, 9.36.

The second product, (±) 5o HCl, was also isolated in 10% yield after therecrystallization of the hydrochloride salt from 2-propanol:ether (1:1)as a white solid; mp 243-245° C. (d); ¹H NMR (200 MHz, CDCl₃) δ1.10-1.50(m, 4H), 1.55-2.20 (m, 8H), 2.90-3.20 (m, 3H), 3.10 (s, 3H), 3.44 (m,1H), 3.65 (d, J=13.5 Hz, 1H), 3.90 (m, 1H), 4.65 (brd, 2H), 7.70 (s,1H), 7.82 (s, 2H). Anal. Calcd for C₂₀H₂₆F₃N₃O₃.HCl.H₂O: C, 51.34; H,6.25; N, 8.98. Found: C, 51.69; H, 6.24; N, 8.89.

EXAMPLE 117(±)-trans-2-Trifluoromethyl-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-phenylacetamideHydrochloride [(±) 5p HCl] ADL-01-0114-7

The compound was prepared from 2-trfluoromethylphenylacetic acidfollowing the Example II. The hydrochloride salt was made from 1Metherial HCl and recrystallized from 2-propanol:ether (1:1) to give (±)5p HCl in 20% yield as a white solid; mp 282-284° C. (d); ¹H NMR (200MHz, CDCl₃) δ1.20-1.50 (m, 4H), 1.55-2.30 (m, 8H), 3.85-3.04 (m, 2H),3.08 (s, 3H), 3.10-3.27 (m, 1H), 3.40-3.60 (m, 1H), 3.90 (m, d, J=14.5Hz, 2H), 4.26 (d, J=14.7 Hz, 1H), 4.63 (m, 1H), 7.26 (t, J=8.0 Hz, 1H),7.45 (t, J=8.0 Hz, 1H), 7.60 (t, J=7.5 Hz, 2H). Anal. Calcd forC₂₀H₂₇F₃N₂O.HCl: C, 59.33; H, 6.97; N, 6.92. Found: C, 59.28; H, 6.73;N, 6.84.

Nitration of 2-trifluorometylphenyl acetic acid

Preparation of 4-nitro-2-trifluoromethylphenyl acetic acid[4,R=4-NO₂(2-CF₃)—C₆H₄CH₂]

The nitration of 2-trifluorophenylacetic acid as depicted in Scheme IIIgave mostly the corresponding 4-nitro derivative and only a trace amountof 6-nitro compound was detected in the proton NMR; ¹H NMR (200 MHz,CDCl₃) δ3.90 (s, 2H), 7.55 (d, J=8.4 Hz, 1H), 8.35 (dd, J=2.4, 8.0 Hz,1H), 8.50 (d, J=2.4 Hz, 1H). The compound was used directly into thefollowing coupling reaction.

EXAMPLE 118(±)-trans-4-Nitro-2-trifluoromethyl-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-phenylacetamideHydrochloride [(±) 5q HCl] ADL-01-0116-2

The compound was prepared following the coupling method described inExample 109 from 4-nitro-2-trfluorophenylacetic acid. The hydrochloridesalt was prepared by known method and recrystallized from2-propanol:ether (1:1) to give (±) 5q HCl as a beige colored solid in37% yield; mp 265-267° C. (d); ¹H NMR (200 MHz, CDCl₃) δ1.15-1.45 (m,4H), 1.50-2.30 (m, 8H), 2.85-3.20 (m, 3H), 3.05 (s, 3H), 3.45 (m, 1H),3.90 (m, d, J=14.0 Hz, 2H), 4.60 (brd, 2H), 8.00 (d, J=8.0 Hz, 1H), 8.25(dd, J=2.4, 8.0 Hz, 1H), 8.40 (d, J=2.4 Hz, 1H). Anal. Calcd forC₂₀H₂₆F₃N₃O₃.HCl: C, 53.39; H, 6.05; N, 9.34. Found: C, 53.29; H, 5.93;N, 9.17.

EXAMPLE 119(±)-trans-4-Amino-2-trifluoromethyl-N-methyl-N-[2-(1-pyrrolidinyl)cycohexyl]-phenylacetamideHydrochloride [(±) 5r 2HCl] ADL-01-0142-8

The compound was prepared from free base (±) 5q following the reductionprocedure described for the preparation of (±) 5h. The free base wasconverted to di-hydrochloride from 1M etherial HCl and recrystallizedfrom CH₂Cl₂:CH₃OH:Et₂O (6:3:1) to give (±) 5r 2HCl as a white solid in68% yield; mp 288-290° C. (d); ¹H NMR (200 MHz, DMSO-d₆) δ1.10-2.20 (m,12H), 2.98 (s, 3H), 3.00-3.30 (m, 4H), 3.50 (m, 1H), 3.80 (d, J=14.5 Hz,1H), 4.20 (d, J=14.8 Hz, 1H), 4.50 (m, 1H), 7.50 (m, 3H). Anal. Calcdfor C₂₀H₂₈F₃N₃O.2HCl: C, 52.65; H, 6.63; N, 9.21. Found: C, 52.67; H,6.52; N, 9.06.

EXAMPLE 120(±)-trans-N-Methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]2,2-dphenylacetamideHydrochloride [(±) 5s HCl] ADL-01-0013-4

The compound was prepared from diphenylacetic acid following the generalprocedure for the preparation of aryl acetamides. The hydrochloride saltwas recrystallized from 2-propanol to give (±) 5s HCl as a white solidin 20% yield; mp 295-297° C. (d); ¹H NMR (200 MHz, CDCl₃) δ1,20-2.40 (m,12H), 2.85-3.15 (m, 2H), 3.00 (s, 3H), 3.25-3.60 (m, 2H), 3.95 (m, 1H),4.75 (m, 1H), 5.70 (s, 1H), 7.35 (m, 10H). Anal. Calcd forC₂₅H₃₂N₂O.HCl.0.25H₂O: C, 71.92; H, 8.09; N, 6.71. Found: C, 72.25; H,8.40; N, 6.52.

EXAMPLE 121(±)-trans-4-Methylsulfonyl-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]phenylacetamideHydrochloride [(±) 5t HCl] ADL-01-0071-9

The compound was prepared from 4-methylsulfonylphenylacetic acid to themethod of Example 109 and the hydrochloride salt was recrystallized fromCH₂Cl₂:ET₂O (1;1) to give (±) 5t HCl as a cream colored solid in 50%yield; mp 152-154° C. (d); ¹H NMR (200 MHz, CDCl₃) δ1.10-2.30 (m, 12H),2.95 (s, 6H), 3.00-3.25 (m, 2H), 3.40 (m, 1H), 3.65 (d, J=14.5 Hz, 1H),3.85 (m, 1H), 4.35 (d, J=14.0 Hz, 1H), 4.67 (m, 1H), 7.45 (d, J=8.0 Hz,2H), 7.80 (d, J=8.0 Hz, 2H). Anal. Calcd for C₂₀H₃₀N₂O₃S.HCl.1.5H₂O: C,54.35; H, 7.75; N, 6.34. Found: C, 54.20; H, 7.38; N, 6.15.

Preparation of compounds 4a through 4l of formula IVA is according toScheme O.

The chiral compounds were prepared from the enantiomeric pure diamine B

EXAMPLE 4a(Z)-4-[2-((±)-trans-2-Amino-4,5-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]phenylaetamido)]4-oxo-2-butenoicacid

To a solution of(±)-trans-2-amino-4,5-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-phenylacetamide3(0.12 g, 0.312 mmol) in anhydrous THF (2.5 mL) under anitrogenatmosphere was added maleic anhydride (0.03 g, 0.312 mmol). The reactionmixture was stirred at room temperature for 3 days. The precipitatedsolid was filtered off, washed with anhydrous THF, and dried to give 4a(0.088 g, 58%); mp 246-248° C. (d); MS (FAB) 482 (M⁺). Anal. Calcd. forC₂₃H₂₉Cl₂N₃O₄.H₂O: C, 55.20; H, 6.24; N, 8.40. Found: C, 55.32; H, 6.01;N, 8.09.

Ref.

3. de Costa, B. R. et. al. FEBS Lett. 249, 178-182 (1989).

EXAMPLE 4b(Z)-4-[2-((±)-trans-2-Amino-4-trifluoromethyl-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]-phenylaetamido)]4-oxo-2-butenoicacid

The compound 4b was prepared from(±)-trans-2-amino-4-trifluoromethyl-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]phenylaetamide¹following the above procedure in 60% yield; mp 256-258° C.; ¹H NMR (300MHz, DMSO-d₆) δ1.15-2.18 (m, 12H), 3.01 (s, 3H), 3.15-4.10 (m, 7H), 4.50(m, 1H), 5.95 (d, J=15.0 Hz, 1H), 6.35 (d, J=14.5 Hz, 1H), 7.37 (m, 2H),8.16 (s, 1H). Anal. Calcd for C₂₄H₃₀F₃N₃O₄: C, 59.87; H, 6.28; N, 8.37.Found: C, 59.64; H, 6.14; N, 8.57.

EXAMPLE 4c(±)-trans-2-N-Methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-pyridylacetamidedihydrochloride

The compound 4c was prepared from 2-pyridyl acetic acid hydrochlorideand (±)-trans-2-pyrrolidinyl-N-methylcyclohexylamine³ following thegeneral procedure in 37% yield; mp 264-266° C. (d); ¹H NMR (300 MHz,DMSO-d₆) δ1.10-2.00 (m, 12H), 3.04 (s, 3H), 3.15-4.70 (m, 5H), 4.30 (d,J=16 Hz, 1), 4.55 (m, 1H), 4.67 (d, J=16.0 Hz, 1H), 7.82 (t, J=7.5 Hz,1H), 8.10 (d, J=7.8 Hz, 1H), 8.55 (t, J=7.5 Hz,1H), 8.88 (d, J=7.0 Hz,1H). Anal. Calcd for C₁₈H₂₇N₃O.2HCl.0.25H₂O: C, 57.07; H, 7.85; N,11.09. Found: C, 57.04; H, 7.48; N, 10.69.

EXAMPLE 4d(±)-trans-3-N-Methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-5-bromo-pyridylacetamidehydrochloride

The compound 4d was prepared 5-bromo-3-pyridyl acetic acid in 77% yield;mp 130-132° C.; ¹H NMR (free base 200 MHz, CDCl₃) δ1.00-2.00 (m, 12H),2.88 (s, 3H), 2.35-2.77 (m, 5H), 3.75 (m, 2H), 4.50 (m, 1H), 7.65 (bs,1H), 8.30 (bs, 1H), 8.67(s, 1H). Anal. Calcd for C₁₈H₂₆BrN₃O.HCl: C,51.87; H, 6.53; N, 10.08. Found: C, 51.48; H, 6.11; N, 9.70.

EXAMPLE 4e(±)-trans-3,5-Di-Trifluoromethyl-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]phenylacetamidehydrochloride

Prepared from 3,5-di-trifluoromethyl-phenyl acetic acid in 27% yield; mp211-213° C.; ¹H NMR (300 MHz, CDCl₃) δ1.20-2.25 (m, 12H), 3.04 (s, 3H),3.00-3.35 (m, 3H), 3.50 (m, 1H), 3.80 (d, J=15.0 Hz, 1H), 4.00 (m, 1H),4.60 (m, 2H), 7.75 (s, 1H), 7.84 (s, 2H). Anal. Calcd forC₂₁H₂₆F₆N₂O.HCl: C, 53.34; H, 5.75; N, 5.92. Found: C, 53.14; H, 5.74;N, 5.76.

EXAMPLE 4f(±)-trans-3-N-Methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-(trans-3-furyl)acetamidehydrochloride

The compound 4f was prepared from trans-3furan acrylic acid in 56%yield; mp 164-166° C. (d); ¹H NMR (200 MHz, CDCl₃) δ1.20-2.25 (m, 12H),3.15(s, 3H), 2.75-3.95 (m, 4H), 4.70 (m, 2H), 6.57 (bs, 1H), 6.65 (d,J=15.0 Hz, 1H), 7.34 (s, 1H), 7.46 (d, J=15.2 Hz, 1H), 7.55 (s, 1H).Anal. Calcd for C₁₈H₂₆N₂O₃.HCl.0.5H₂O: C, 62.15; H, 8.11; N, 8.05.Found: C, 61.94; H, 8.01; N, 7.91.

EXAMPLE 4a(±)-trans-2-Methoxy-3-methylsulfamoyl-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]phenylacetamidehydrochloride

The compound 4g was prepared from 2-methoxy-3-methylsulfamoyl-phenylacetic acid (prepared from methyl 2-methoxy phenyl acetic acid by theprocedure reported earlier) in 45% yield; mp 168-170° C.; ¹H NMR (200MHz, CDCl₃) δ1.15-2.20 (m, 12H), 2.52 (d, J=2.5 Hz, 3H), 2.76 (s, 3H),2.40-2.70 (m, 4H), 3.58 (d, J=5.0 Hz, 1H), 3.79 (s, 3H), 3.84 (d, J=4.8Hz, 1H), 4.75 (m, 2H), 6.84 (d, J=8.7 Hz, 1H), 7.65 (m, 2H). Anal. Calcdfor C₂₁H₃₃N₃O₄S.HCl.0.5H₂O: C, 53.78; H, 7.52; N, 8.96. Found: C, 53.80;H, 7.50; N, 8.90.

EXAMPLE 4h(±)-trans-3-N-Methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]indoleacetamidehydrochloride

Prepared from indole 3-acetic acid in 61% yield; 262-264° C.; ¹H NMR(300 MHz, DMSO-d₆) δ1.20-2.15 (m, 12H), 2.95 (s, 3H), 2.97-3.55 (m, 4H),3.83 (s, 2H), 4.55 (m, 2H), 6.96 (t, J=7.5 Hz, 1H), 7.02 (t, J=7.0 Hz,1H), 7.17 (s, 1H), 7.31 (d, J=8.0 Hz, 1H), 7.57 (d, J=7.8 Hz, 1H). Anal.Calcd for C₂₁H₂₉N₃O.0.9HCl: C, 67.75; H, 8.10; N, 11.29. Found: C,67.78; H, 8.12; N, 11.22.

EXAMPLE 4i(±)-trans-4-Fluoro-3-methylsulfamoyl-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]phenylacetamidehydrochloride

The compound 4i was prepared from 4-fluroro-3-methylsulfamoyl phenylacetic acid in 48% yield; mp 265-267° C.; ¹H NMR (200 MHz, DMSO-d₆)δ1.30-2.20 (m, 12H), 2.60 (s, 3H), 3.06 (s, 3H), 3.15-3.80 (m, 4H), 3.91(d, J=15.0 Hz, 1H), 4.20 (d, J=15.5 Hz, 1H), 4.65 (m, 1H), 7.50 (t,J=8.0 Hz, 1H, 7.75 (m, 2H). Anal. Calcd for C₂₀H₃₀FN₃O₃S.HCl.H₂O: C,51.55; H, 7.14; N, 9.02. Found: C, 51.93; H, 6.81; N, 8.70.

EXAMPLE 4j N-[1S,2S-trans-4-Trifluoromethyl-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-phenylacetamido]glycineHydrochloride 1S,2S-trans-2-Nitro-4-trifluoromethyl-N-methyl-N-[2-(1-pyrolidinyl)cyclohexyl]-phenylacetamidehydrochloride

To a solution of (1S,2S-(±)-trans-2-pyrrolidinyl-N-methylcyclohexylamine³ (1.9 g, 10.42 mmol)in anhydrous CH₂Cl (25 mL) under a nitrogen atmosphere was added2-nitro-4-trifluorophenyl acetic acid¹ (3.9 g, 15.63 mmol) and pyridine(o.42 mL, 5.21 mmol). The reaction mixture was cooled to 0° C. and addedDCC (4.3 g, 20.84 mmol) in one portion and stirred the mixture for 3.5h. The TLC [solvent system: CH₂Cl₂:CH₃OH:28% NH₄OH (95:5:2)] showed nostarting material was present. The DCU was removed by filtration and thesolvent was removed under reduced pressure. The residue was partitionedbetween 10% citric acid (100 mL) and ether (100 mL). The ether layer wasdiscarded and the aqueous layer was washed with ether twice. The aqueouslayer was then made alkaline from 28% ammonia hydroxide and the productwas extracted with CH₂Cl₂. The organic layer was separated, dried overanhydrous Na₂SO₄, and evaporated to dryness to give the crude product.The hydrochloride salt was prepared from 1M etherial HCl andrecrystallized from 2-prppanol:ether (1:1) to give the desired product,4.2 g (97%); [α]^(18.8) ₅₈₉−20.42° (c 1.01, CH₃OH); ¹H NMR (300 MHz,CDCl₃) δ1.20-2.35 (m, 12H), 298-3.28 (m, 4H), 3.20 (s, 3H), 3.45 (m,1H), 3.98 (m, 1H), 4.45 (d, J=14.0 Hz, 1H), 4.70 (d, J=14.5 Hz, 1H),7.80 (d, J=8.7 Hz, 1H), 7.92 (d, J=8.0 Hz, 1H), 8.34 (s, 1H). Thecompound was used directly into the following reaction.

1S,2S-trans-2-Amino-4-trifluoromethyl-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]phenyl-acetamidehydrochloride

The above 2-nitro compound as hydrochloride salt (4.1 g, 9.09 mmol) wasdissolved in methanol (30 mL), added PtO₂ (0.4 g), and hydrogenated atroom temperature atmospheric pressure for 1 h. The catalyst was filteredoff, washed with hot methanol and the combined filtrate was evaporatedto dryness. The residue was recrystallized from ethyl acetate to givethe 2-amino compound as hydrochloride salt, 3.2 g (84%); [α]^(18.6)₅₈₉−6.48° (free base, c 0.51, CH₃OH); ¹H NMR (300 MHz, CDCl₃) δ1.25-2.35(m, 12H), 3.00-3.30 (m, 4H), 3.15 (s, 3H), 3.45 (m, 1H), 3.97 (m, 1H),4.35 (m, 1H), 4.80 (m, 1H), 6.90 (s, d, 2H), 7.05 (d, J=7.5 Hz, 1H). Thefree base of the 2-amino compound was used to prepare the targetcompound.

The 2-amino compound (free base, 2.8 g, 7.30 mmol) was dissolved inanhydrous THF (20 mL) under a nitrogen atmosphere.N,N-Diisopropylethylamine (1.88 g, 14.60 mmol) was added at roomtemperature followed by t-butyl bromoacetate (2.14 g, 11.0 mmol) and thereaction mixture was stirred at room temperature for 3 days. The TLC[solvent system: CH₂Cl₂:CH₃OH:28% NH₄OH (95:5:2)] showed still startingmaterial was pesent, the reaction mixture was heated to 60-70° C.(oil-bath temperature) for 48 h after the addition ofN,N-diisopropylethylamine (1.88 g, 14.60 mmol) and by t-butylbromoacetate (2.14 g, 11.0 mmol). The reaction mixture was cooled toroom temperature and the solvent was removed under reduced pressure. Theresidue was then re-dissolved in CH₂Cl₂, washed with water, 10% aqueousNaHCO₃, saturated salt solution, and dried over anhydrous Na₂SO₄.Removal of solvent at reduced pressure resulted the crude product whichwas purified on a silica gel column [solvent system: CH₂Cl₂:CH₃OH:28%NH₄OH (98:2:2)] to the desired t-butyl ester, 2.3 g (63%), as a foam;%); [α]^(19.5) ₅₈₉−9.5° (c 1.0, CH₂Cl₂); the chiral purity (>90%) of thecompound was checked on ChiralPak® AD column; MS (FAB) 498 (M+1); ¹H NMR(300 MHz, CDCl₃) δ1.10-2.00 (m, s, 21H), 2.45-2.75 (m, 4H), 2.90 (s,3H), 3.70 (m, 2H), 3.88 (m, 2H), 4.50 (m, 1H), 6.65 (s, 1H), 6.90 (d,J=7.0 Hz, 1H), 7.20 (d, J=7.5 Hz, 1H).

The t-butyl ester (2.1 g, 4.22 mmol) was dissolved in acetic acid (20mL) and added 4N aqueous HCl (25 mL). After addition of 4 drops ofp-anisole, the raction mixture was stirred at room temperature for 4days. The solvent was removed under reduced pressure and the residue wasre-dissolved in minimum amount of acetonitrile and added excess ofether. The resulting solid was filtered, washed with ether, and dried.Re-crystallization from acetonitrile:ethylacetate (1:1) gave compound 4j(1.0 g, 50%); mp 176-178° C.; [α]^(20.5) ₅₈₉+6.5° (c 0.5, CH₂Cl₂); ¹HNMR (300 MHz, DMSO-d₆) δ1.10-2.05 (m, s, 12H), 2.70 (s, 3H), 2.98-3.30(m,4H), 3.40-4.15 (m, 6H), 6.65 (s, 1H), 6.82 (d, J=7.5 Hz, 1H), 7.10(d, J=7.5 Hz, 1H). Anal. Calcd for C₂₂H₃₀FN₃O₃.HCl: C, 55.29; H, 6.54;N, 8.79. Found: C, 55.61; H, 6.76; N, 8.97.

EXAMPLE 4k N-[1R,2R-trans-4-Trifluoromethyl-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-phenylacetamido]glycineHydrochloride

The compound was prepared from (1R,2R)-(−)-trans-2-pyrrolidinyl-N-methylcyclohexyl-amine³ (1.9 g, 10.42mmol) following the above procedures in 36% yield; [α]^(20.5) ₅₈₉−7.4°(c 0.52, CH₂Cl₂). Anal. Calcd for C₂₂H₃₀FN₃O₃.HCl.0.25CH₃CN: C, 55.35;H, 6.55; N, 9.32. Found: C, 55.78; H, 6.81; N, 9.24.

In a composition aspect, the kappa agonist compounds of the presentinvention are formulated into parenteral, local and topicalformulations.

The compositions are formulated as injectables, as oral and rectalformulations for systemic administration, and for local and topicaladministration as creams, aqueous or non-aqueous suspension, lotions,emulsions, suspensions or emulsions containing micronized particles,gels, foams aerosols, solids and other suitable vehicles for applicationto the skin, eyes, lips and mucosa, as suppositories or cream forvaginal administration, and as combinations with bandages, patches,bioadhesives and dressings. The compounds may be formulated incombination with other agents, such as local anesthetics and othertherapeutic agents. The other agents may be mixed in the compositionsare provided and administered prior to, simultaneously with orsubsequent to administration of the compositions provided for themethods herein. Such agents include, but are not limited to:antibiotics, including cephalosporins, β-lactams, tetracyclines,vancomycins, sulfas and aminoglycosides; antivirals, including acylovir;and antifungals including clotrimazole.

In a method aspect the present invention provides method to treatpruritus by applying an amount of a compound or composition to a mammalto ameliorate or eliminate pruritus. inflammatory mediators in thejoint, (ii) release of neuropeptides from afferent fibers in the jointcavity, and (iii) increased primary afferent outflow from group II, III,IV sensory fibers [Schaible et al. (1993) Pain 55: 5-54]. An importantresult of this cascade is that there is an augmentation in the responseof small, lightly myelinated and unmyelinated afferents to low intensitystimuli. In this manner, the peripheral nerve innervating inflamedtissue can evoke an exaggerated behavioral response to otherwiseinnocuous stimuli i.e., a state of hyperalgesia. Thus, inflammation ofthe knee joint will result in increased spontaneous afferent activity,the appearance of an exaggerated discharge with joint flexion andextension [Schaible et al. (1995) J. Neurophysiol. 54: 1109-1122] andsigns of a pain-associated autonomic reaction [Sata et al (1984)Neurosci. Lett. 52: 55-60].

Injection of a mixture of kaolin and carrageenan into the knee jointinduces an experimental arthritis. As exemplified below, this treatmentwas characterized by a reliable increase in joint volume andcircumference. In the unanesthetized rat, these joint changes wereaccompanied by a tendency to avoid weight bearing, suggesting an ongoingpain state. According to electrophysiological studies, in the course ofthe development of this acute arthritis, C and Ad units normallyresponding only to extreme joint distortion become activated by slightmovement [Schaible et al. (1985) J. Neurophysiol. 54: 1109-1122]. Spinalneurons with knee joint receptive fields in the deep dorsal horn of thespinal cord show clear development of hyperexcitability with the acuteinflammation in the joint [Neugebauer et al. (1993) J. Neurosci. 70:1365-1377]. This sensitization of group III and IV fibers was observedwithin 2-3 hours after injection of kaolin and carrageenan into the kneejoint, a time course that closely matches the time course of thedevelopment of hyperalgesia in the rat knee joint compression model.These observations indicate that spinal cord neurons and joint primaryafferent fibers become sensitized and may underlie hyperalgesia observedin this arthritic state. Such afferent input may drive autonomicresponses that are typically associated with the processing of inputfrom afferents typically activated by stimuli generated by the localinflammatory state. In addition to the above-mentioned inflamed kneejoint mechanism, the blood pressure (BP) changes might also be evokedreflexively by afferent neural activity from receptors located in theskeletal muscle [Williamson et al. (1994) J. Physiol. 475: 351-357].This response is dependent on the changes in intramuscular pressure andthe quality of muscle mass compressed. This particular mechanicalreflex, however, appears to operate independently of the pain responseand appears to play a minor role in the exemplified experiments, asinflation of the cuff on the left normal knee joint had no effect uponBP. In any case, it is possible that overflow of the carrageenan fromthe joint capsule may serve to render surrounding tissue inflamed aswell. Sensitization of C and A units was observed in the ratgastrocnemius muscle by infiltration with carrageenan [Handwerker et al.(1991) Pain and Inflammation, Proceeding of the VIth World Congress onPain, Bond et al. eds., Elsevier Science Publishers BV, pp. 59-70].Based on these considerations, it appears that compression of theinflamed knee joint yields a noxious stimulus and this in turn activatesa sympathetic response resulting in an increase in BP.

Local inflammation of the knee results in a state where otherwiseinnocuous stimuli results in a prominent autonomic response, includingincreased blood pressure (BP) and heart rate [see, e.g., Sata et al(1984) Neurosci. Lett. 52: 55-60]. Alternatively, neural outflow fromthe inflamed knee is recorded [see, e.g. Neugebauer et al (1993) J.Neurosci. 70: 1365-1377].

An in vitro test that measures spontaneous discharge in injured skin bytopical application may also be used. [see, e.g., Andreev et al. (1994)Neurosci. 58: 793-798].

(c) In vivo Evaluation of Formalin-induced Nociception

Administration of formalin into the paw results in a localizedinflammation and a pain response that is moderate in intensity andcontinuous in duration. Unlike many other assays of nociception, theformalin assay measures tonic pain that is a result of tissue injury,and therefore is a model which is more relevant to clinical pain statesin humans [see Tjolsen et al. (1992) Pain 51: 5-17]. In the rat theresponse to formalin-induced pain consists of spontaneous flinchingbehavior, characterized by paw lifting and paw shaking, and a rapidvibration of the paw after drawing it under the body. The flinchingresponse can be reliably quantitated and exhibits two peaks of activitywhich are indicative of acute and tonic pain [Wheeler-Aceto and Cowan(1991) Psychopharmacology 104: 35-44]. The early or acute phase lastsfrom 0-5 min post-formalin and is followed by a quiescent period lastingapproximately 15 min. The tonic phase occurs from 20-35 min followingformalin injection and is the interval where the number of flinchingresponses is maximal. This model has been characterized in severalspecies [Tjolsen et al. (1992) Pain 51: 5-17] and is sensitive to theanalgesic effects of opiates administered by a variety of routes,including local administration directly into the paw. In addition, thetest is particularly sensitive to the effects of k agonists[Wheeler-Aceto and Cowan (1991) Psychopharmacology 104: 35-44].

Inflammation is induced by subcutaneous injection of 50 ml of a 5%formalin solution into the dorsal surface of the right hind paw of maleSprague-Dawley rats weighing 70-90 g. Injections of drug are given intothe dorsal surface of the paw prior to formalin injection, and flinchingbehavior is quantitated by counting the number of responses that occurduring the tonic phase of pain, lasting from 20-35 min after formalininjection. Results are expressed as the mean percent antagonism offormalin-induced flinching calculated for individual drug-treated,formalin-injected rats using the following formula:

(mean formalin response−mean saline response)−individual response/×100mean formalin response−mean saline response

The mean formalin response is the mean behavioral score ofvehicle-treated and formalin-injected rats. The mean saline response isthe pooled behavioral score from rats injected with 50 ml of saline intothe paw.

(d) Randall-Selitto Test

Numerous variations and exemplifications of this assay are known tothose of skill in this art [see, Randall et al (1957) Arch. Int.Pharmacodyn. 111: 409-419; see, also, e.g., U.S. Pat. Nos. 5,434,292,5,369,131, 5,345,943, 5,242,944 and 5,109,135.

The pain threshold is measured in this method as the amount of pressurein g required to induce a flight reaction (struggle) when applied to thefoot of an experimental animal exhibiting hyperalgesia, typically aninflamed paw, compared to a control, such as the same or equivalentanimal in the absence of the inflammation, and/or in the absence of atest compound. Incremental pressure is applied to the paw with awedge-shaped blunt piston onto the dorsal surface of the hind paw bymeans of a paw pressure analgesia meter. The pressure required to elicitpaw withdrawal, the paw pressure threshold (PPT), is determined.

Stein and coworkers [Stein et al. (1988) Pharmacol. Biochem. Behav. 31:445-451; Stein et al. (1989) J. Pharmacol. Exp. Ther. 248: 1269-1275]have developed a model of peripheral inflammation and hyperalgesia inrats, which supports the role of opiates in mediating peripheralanalgesia. In this protocol, modified Freund's adjuvant is used as theinflammatory stimulus, and the paw pressure test is used to assess theresponse of the rat to a painful pressure stimulus. The model issensitive to opiate agonists of the m, d and k subtypes, which produceanalgesia upon administration [Artonijevic et al. (1995) J. Neurosci.15: 165-172; Stein et al. (1988) Neurosci. Lett. 84: 225-228; Stein etal. (1989) J. Pharmacol. Exp. Ther. 248: 1269-1275]. Histologicalverification of opiate receptor localization and density have confirmedthat peripheral opiate receptors are accessible on primary afferentnerve fibers and are upregulated following inflammation [Hassan et al.(1993) Neuroscience 55: 185-193; Przewlocki et al. (1992) Neuroscience48: 491-500].

Experiments are conducted in rats weighing 150-250 g at the time ofinoculation. Modified Freund's complete adjuvant (FCA) is used as theinflammatory stimulus. Rats are administered an i.pl. injection of theFCA suspension into the right hind foot. Hyperalgesia andantinociception are evaluated using the paw pressure test. The rat isgently restrained and incremental pressure is applied to the paw with awedge-shaped blunt piston onto the dorsal surface of the hind paw bymeans of a paw pressure analgesia meter. The pressure required to elicitpaw withdrawal, the paw pressure threshold (PPT), is determined. Acutoff pressure of 250 g is used to avoid undue stress and pain to theanimal. Baseline responding is established by determining the average ofthree consecutive trials separated by 10 sec. The same procedure isconducted on the contralateral side and the sequence of sides isalternated between animals to control for order effects. Typicallyinjections are not made in the contralateral (noninflamed) paw; however,in selected cases drugs may be administered to the contralateral paw toevaluate the potential for drug effects in the absence of inflammation.

Analgesic activity is determined by expressing the increase in PPTresulting from the effect of the drug as a percentage of basalpreinjection thresholds.

Hyperalgesia can also be produced by inflammatory stimuli such as yeastor carrageenan, endogenous inflammatory mediators such as bradykinin orprostaglandins, or other types of chemical irritants [see Hargreaves andJoris (1993) APS Journal 2: 51-59].

(e) Acetic Acid-induced Writhing

This test identifies novel agents which exhibit peripheral analgesicactivity against visceral or chemical pain [see Barber and Gottschlich(1986) Med. Res. Rev. 12: 525-562; Ramabadran and Bansinath (1986)Pharm. Res. 3: 263-270]. Injection of acetic acid into the peritonealcavity is used as the noxious stimulus, and the number of writhingresponses that occur in response to acetic acid are counted in order toquantify the response to pain. Compounds which possess analgesicactivity reduce the number of writhing responses that occur. Opiateagonists of the m and k subtype exhibit analgesic activity in this model[Barber and Gottschlich (1986) Med. Res. Rev. 12: 525-562; Millan (1990)Trends Pharmacol. Sci. 11: 70-76]. Novel compounds which demonstratepotency and efficacy in this assay are potential drugs for the treatmentof various pathological conditions involving peripheral pain.

The writhing assay is adapted from the procedure originally described byTaber et al. [(1969) J. Pharmacol. Exp. Ther. 169: 29-38], using maleCF-1 mice weighing 20-25 g. Animals are treated with various doses ofdrugs prior to the administration of an i.p. injection of 0.6% aceticacid solution. Mice are then placed into observation chambers and thenumber of writhing responses, as defined by a full hindlimb extensionand retraction, are recorded.

The mean number of writhing responses is calculated for vehicle-treatedcontrol mice, and the percent inhibition (% I) of writhing is calculatedfor each mouse that is treated with drug using the following formula:

% I=100×(mean control writhing responses−individual test responses)/meancontrol writhing responses

(f) Hyperalgesia Induced by Tape Stripping

The objective of this assay is to identify novel agents which exhibitperipherally-mediated analgesia in circumstances, such as burns andabrasions, which lead to hyperalgesia. In such injuries, the loss of thestratum corneum is followed by an inflammatory response (erythema) and apainful response to otherwise innocuous stimuli. Removal of the stratumcorneum by repeated application and removal of cellophane tape, termedtape stripping, has been shown to be a simplified model of theseinjuries, which share characteristics of first degree burns [see Flynn(1985) Percutaneous Absorption, R. L. Bronaugh and H. I. Maibach, eds.,Marcel Dekker Inc., pp. 1842]. This method of barrier disruption avoidsthe application of potentially toxic chemicals and permits evaluation ofperipheral analgesics following topical administration because tapestripping removes the barrier to effective topical therapy (the stratumcorneum) while simultaneously resulting in inflammation andhyperalgesia. Tape stripping has been validated in humans as a model forthe testing of topical agents [Pershing et al.(1994) Antimicrob. AgentsChemother. 38: 90-95; Roy and Flynn (1990) Pharm. Res. 7: 842-847].

Experiments are conducted in male Sprague-Dawley rats weighing 250-500 gat the time of treatment. After anesthesia of the rat withketamine-xylamine, a 1-3 cm² patch of rat skin is treated by repeatedapplication and removal of tape. This procedure results in removal ofthe stratum corneum as determined by a glistening appearance of theskin. The tape stripped skin is evaluated for a visible erythema and forsensitivity to contact by heat or pressure stimuli using a focused beamof light, by testing in the paw pressure apparatus or by touch with vonFrey hairs. The diameter of the von Frey hairs will be selected based ona diameter which causes no response in control rats but has a readilydetectable response in treated rats.

Typically analgesics will be formulated in a suitable topical medium andapplied to the treated skim. Some rats will receive only the topicalmedium without analgesic to control for an effect of the topical mediumalone. The presence of analgesia is determined by the latency to respondto the heat stimulus or by response to touch or pressure.

Pharmacological activities of compounds of the present invention areshown in Tables I, IA, II, IIA, III, IIIA, IV and IVA in which K_(i): nM(³H-diprenorphin and ³H-U-69, 593) show in vitro binding assay resultsas described in “(a) In vitro binding assay (Primary Screen); and A₅₀(μg); i.paw show in vivo formalin-induced nociception results asdescribed in “(c) In vivo evaluation of formalin-induced nociception”.

TABLE I Compounds of Formula I R-3a-I R,S-8a-e, R = SO₂CH₃ R,S-9a-f, R =CO₂CH₃ R,S-10a-f, R = COCH₃

Late Phase Ki, nM Formalin Compounds R Ar ³H-Diprenorphin ³H-U-69,593A₅₀ (mg);i.paw GR 89696 CO₂CH₃ 3,4-Cl₂ 0.095, 0.10  1.6, 1.5 0.35(0.20-0.62) (R) ADL-01-0143-6 Bn 3,4-Cl₂ 57, 38 9.3 53% @ 300 (R-1)ADL-01-0047-9 H 3,4-Cl₂ 14, 17 1.5, 1.3 57% @ 300 (R-2) ADL-01-0039-6SO₂CH₃ 3,4-Cl₂ 0.2, 1.3 0.19, 0.5  14 (5.6-29) (R-3a) ADL-01-0040-4CH₂CO₂t-Bu 3,4-Cl₂ 30% @ 1 μM 75% @ 1 μM 75% I @ 1 μM (R-3b)ADL-01-0042-0 CH₂CO₂H 3,4-Cl₂ 62% @ 1 μM 23, 21 26% @ 300 (R-3c)ADL-01-0048-7 (R-3d)

3,4-Cl₂ 36% @ 1 μM 379, 249 Not tested. ADL-01-0041-2 (R-3e)

3,4-Cl₂ 39% @ 1 μM 37, 28 22% A @ 300 ADL-01-0148-5 COCH₃ 3,4-Cl₂ 4.2,1.4 0.11, 0.14 95% @ 300 (R-3f) ADL-01-0149-3 PO(OEt)₂ 3,4-Cl₂ 99, 331.3, 1.4 54% @ 300 (R-3g) ADL-01-0150-1 COCF₃ 3,4-Cl₂ 6.9, 1.8 0.26,0.16 94% @ 300 (R-3h) ADL-01-0151-9 CONH₂ 3,4-Cl₂ 56, 29 2.9 68% @ 300(R-3i) ADL-01-0156-8 CHO 3,4-Cl₂ 96% @ 1 μM  0.40 65% @ 300 (R-3j)ADL-01-0165-9 SO₂-Tol 3,4-Cl₂ 120    6.2 24% @ 300 (R-3l) ADL-01-0135-2SO₂CH₃ 3,4-Cl₂ 5.4, 4.0 0.37, 0.65 96% @ 300 (R,S-8a) ADL-01-0117-0SO₂CH₃ p-SO₂CH₃ 41% @ 1 uM 20, 31 Not tested (R,S-8b) ADL-01-0119-6SO₂CH₃ o-NO₂ 15% @ 1 μM 51% @ 1 μM Not tested (R,S-8c) ADL-01-0120-4SO₂CH₃ p-CF₃ 16, 17 1.3, 1.9 97% @ 300 (R,S-8d) ADL-01-0134-5 SO₂CH₃3-indole 74% 5.3, 3.2 Not tested (R,S-8e) ADL-01-0092-5 CO₂CH₃ p-SO₂CH₃11   0.37, 0.42 46% @ 300 (R,S-9a) ADL-01-0094-1 CO₂CH₃ p-CF₃  0.490.076, 0.13 98% @ 300 (R,S-9b) ADL-01-0095-8 CO₂CH₃ 3-indole 3.0 0.27,0.40 95% @ 300 (R,S-9c) ADL-01-0096-6 CO₂CH₃ o-NO₂ 37   0.74, 0.73 93% @300 (R,S-9d) ADL-01-0097-4 CO₂CH₃ o-OCH₃ 7.3 0.46, 1.3  98% @ 300(R,S-9e) ADL-01-0098-2 CO₂CH₃ o-NH₂ 4.6, 3.2 0.67, 0.41 97% @ 300(R,S-9f) ADL-01-0144-4 COCH₃ p-SO₂CH₃ 27% 2.3 6% @ 300 (R,S-10a)ADL-01-0145-1 COCH₃ p-CF₃ 26, 24 2.0 89% @ 300 (R,S-10b) ADL-01-0157-6COCH₃ o-CF₃ 45% @ 1 μM 16   Not tested (R,S-10c) ADL-01-0158-4 COCH₃m-NO₂ 94% @ 1 μM  0.72 Not tested (R,S-10d) ADL-01-0163-4 COCH₃ o-NO₂541    24   Not tested (R,S-10e) ADL-01-0159-2 COCH₃ p-NO₂ 59% @ 1 μM2.4 Not tested (R,S-10f) ADL-01-0093-3 Bn p-CF₃ 2.2, 2.4 0.39, 0.57 92%@ 300 (R,S-11)

TABLE IA Compounds of Formula IA

Formalin (% A @ 300 mM) Ki(nM) i. paw or R Ar R′ R″ n X(³H)-Diprenorphin A₅₀ mg/kg s.c. 1a CO₂CH₃

H H 1 CH₂ 248   Not tested 1b CO₂CH₃

H H 1 CH₂ 7  Not tested 1c CO₂CH₃

H H 1 CH₂ 65% @ 1 mM 69% @ 300 1d CO₂CH₃

H H 1 CH₂  7.6 77% @ 300 1e CO₂CH₃

H H 1 CH₂ 14   55% @ 300 1f CO₂CH₃

H H 1 CH₂ 53.5 Not tested 1g COCF₃

H H 1 CH₂  5% @ 1 mM Not tested 1h COCF₃

H H 1 CH₂ 50   100% @ 300  1i CO₂CH₃

H CO₂CH₃ 2 N 12% @ 1 mM Not tested 1j CO₂CH₃

H

1 CH 13   Not tested 1k CO₂CH₃

H 1 CH 51.5 95% @ 300 1l (R,S) CO₂CH₃

H 1 CH  3.5 1.7 1m CO₂CH₃

H 1 CH 49.5 1.7 1n CO₂CH₃

H 1 CH 12% @ 1 mM Not tested 1o CO₂CH₃

H 1 CH 133   41% @ 300 1p CO₂CH₃

H 1 CH 11   Not tested 1q CO₂CH₃

H

1 CH  5.2 98% @ 300 1r COCH₃

H H 1 CH 43% @ 1 mM Not tested 1s COCH₃

H H 1 CH 53% @ 1 mM Not tested 1t COCH₃

H H 1 CH  1% @ 1 mM Not tested 1u COCH₃

H

1 CH 1780    Not tested 1v COCH₃

H

1 CH  4.3 70% @ 300 1w COCH₃

H

1 CH 1156    60% @ 300 1x COCH₃

H 1 CH 36% @ 1 mM Not tested 1y COCH₃

H 1 CH 45% @ 1 mM Not tested 1z COCH₃

H 1 CH 102   71% @ 300 1aa COCH₃

H 1 CH  % @ 1 mM Not tested 1bb COCH₃

H 1 CH 11% @ 1 mM 46% @ 300 1cc COCH₃

H 1 CH 22% @ 1 mM 10% @ 300 1dd CHO

H H 1 CH 13% @ 1 mM Not tested 1ee

H H 1 CH 58.9 1.0 1ff allyl

H H 1 CH  0.58 98% @ 300 1gg COCH₃

H H 1 CH 27% @ 1 mM Not tested 1hh CHO

H H 1 CH  0% @ 1 mM Not tested 1ii (S,S) CO₂CH₃

H 1 CH 21.5 60% @ 300 1jj SO₂CH₃

H

1 CH 11.5 49% @ 300 1kk SO₂CH₃

H

1 CH  5.1 52% @ 300 1ll SO₂CH₃

H

1 CH  2.86 52% @ 300 1mm SO₂CH₃

H

1 CH 287   Not tested 1nn SO₂CH₃

H

1 CH  2.33 7.1

TABLE II Compounds of Formula II

K_(i) (nM) Late Phase k [³H]- K_(i) (nM) k Formalin Compounds R, n R′Diprenorphin [³H]U69,593 A₅₀ (mg) ADL-01-0017-2 7-OCH{overscore (₃, n =1)}

4.7 0.8 44% A @ 300 ADL-01-0020-6 7-OCH₃, n = 1

142 20 124 ADL-01-0018-0 7-OH, n = 1

0.6 0.18 7 ADL-01-0021-4 7-OH, n = 1

549 432 Not tested ADL-01-0019-8 7-OCH₂CO₂H, n = 1

40 7 39% @ 300 ADL-01-0029-7 7-NO₂, n = 1

2.8 0.8 65 ADL-01-0034-7 7-NO₂, n = 1

57% @ 1 mM 12.8 40% A @ 300 ADL-01-0031-3 7-NO₂, n = 1

9.6 0.7 891 ADL-01-0032-1 7-NH₂, n = 1

2.2 0.35 19 ADL-01-0052-9 7-N(CH₂CO₂Et)₂, n = 1

4.6 0.68 37% A @ 300 ADL-01-0037-0 7-N(CH₂CO₂tBu)₂, n = 1

7.4 2.8 nM 155 ADL-01-0044-6 7-N(CH₂CO₂H)₂, n = 1

3.8 0.68 232 ADL-01-0070-1 7-NH(CH₂)₂PO₃Et₂, n = 1

6.2 2.2 Not tested ADL-01-0053-7 7-NHPO₃Et₂, n = 1

2.4 0.6 34 ADL-01-0090-9 7-SO₂NCH₃Bn, n = 1 6-OMe

48 8.0 Not tested ADL-01-0099-0 7-SO₂NCH₃Bn, n = 1

200 40 Not tested ADL-01-0051-1 —H, n = 2

8.4 2.8 21% A @ 300 ADL-01-0107-1 R = H, n = 0

12 2.0 80% @ 300 ADL-01-0109-7 R = H, n = 0

46% @ 1 mM 29 Not tested ADL-01-0108-9 R = H, n = 0

29% @ 1 mM 146 Not tested ADL-01-0104-8 R = H, n = 0

5.7 0.74 Not tested ADL-01-0106-3 R = H, n = 0

75% @ 1 mM 9 Not tested ADL-01-0105-5 (±)-Niravoline R = H, n = 0

13 1.8 92% @ 300

TABLE IIA Compound of Formula IIA K_(i) (nM) [³H]- Late Phase CompoundStructure Diprenorphin κ Formalin 2a

28.0 69% @ 300 μg

TABLE III Compounds of Formula III

K_(i) (nM) K_(i) (nM) Late Phase k k Formalin Compounds X R R′[³H]Diprenorphin [³H]U69,593 A₅₀ (mg) ADL-01-0004-0 —H —NO₂ 3-5% p-NO₂)

0.65 0.25 16 ADL-01-0030-5 —H —H

2.9, 9.0 0.7, 1.0 29 ADL-01-0055-2 OH R═H

0.61 0.085 15 ADL-01-0033-9 —H —H

0.2 0.1 5.3 ADL-01-0056-0 OH R═H

0.09 0.07 2.7 mg/ms (i-paw) 0.18 mg/kg (sc) ADL-01-0062-8 —H —H

0.20 0.26 27 ADL-01-0067-7 OH R═H

0.16 0.11 97% @ 300 ADL-01-0084-2 —H —H

0.28 0.08 95% A @ 300 ADL-01-0079-2 —H —H

24% @ 1 mM 1.35 Not tested ADL-01-0115-4 —H —NO₂

35 3.2 Not tested ADL-01-0128-7 —H —NO₂

0.3 0.07 Not tested ADL-01-0129-5 —H —NO₂

31 1.5 Not tested ADL-01-0132-9 —H —NO₂

76% @ 1 mM 6.4 Not tested ADL-01-0133-7 —H —NO₂

25% @ 1 mM 79% @ 1 mM Not tested ADL-01-0138-6 —H —NO₂

19% @ 1 mM 168 Not tested ADL-01-0005-7 —H 2,3-Br₂ 4-NH₂

9.4 4.25 306 ADL-01-0007-3 —H —NH₂

0.14 0.04 0.4 ADL-01-0024-8 —H —H

8.15 1.45 65 ADL-01-0089-1 —H —H

13 0.85 58% @ 300 ADL-01-0103-0 —H —H

22 1.8 52% @ 300 ADL-01-0035-4 —H —H

0.10 0.055 7 ADL-01-0068-5 —H —H

0.09 0.10 0.02 mg/Kg (s.c.) ADL-01-0076-8 OH R═H

0.18 0.12 0.02 mg/kg sc ADL-01-0113-9 —H —NH₂

20 2.6 81% @ 300 ADL-01-0059-0 (EMD 60400) OH R═H

0.8 0.175 33 ADL-01-0136-0 —H —NH₂

61% @ 1 mM 43 Not tested ADL-01-0008-1 —H NH-a-D-Asp

3.65 1.05 72 ADL-01-0009-9 —H NH-a-L-Asp

1.9 0.5 9.1 ADL-01-0010-7 —H NH-a-L-(Asp)₂

2.0 0.67 14 ADL-01-0006-5 —H NH-b-L-Asp

2.3 0.7 47 ADL-03-1066 —H NH-g-D-Glu

62 ADL-01-0011-5 —H —N(SO₂Me)₂

6.45 1.2 58 ADL-01-0060-2 —H —H

57% @ 1 mM 6.4, 8.9 17 ADL-01-0075-0 —H —H

54, 40 6.8, 3.5 8.8 mg/Kg (s.c.) ADL-01-0050-3 —H —H

0.38, 0.45 0.01, 0.09 28 ADL-01-0069-3 —H —H

0.83, 0.49 0.29, 0.43 Not tested ADL-01-0077-6 —H —H

2.2, 3.8 0.64, 0.38 Not tested ADL-01-0112-1 —H —H

63% at 1 mM 10.8 91% @ 300 ADL-01-0127-9 —H —H

198 32 Not tested ADL-01-0126-1 —H —N(SO₂Me)₂

7% @ 1 mM 58% @ 1 mM Not tested ADL-01-0124-6 —H —NHPO₃Et₂

33 48 Not tested ADL-01-0139-4 —H —NHPO₃Et₂

56% @ 1mM 76 Not tested ADL-01-0063-6 (EMD 61753) OH R═H

0.52 0.34 59 mg/ms (I-paw) 28 mg/kg (sc) ADL-01-0023-0 —H —H

25, 18 4.8, 3.0 67 ADL-01-0027-1 —H —H

55, 42, 60 7.7, 15 174 ADL-01-0036-2 —H —H

0.2, 0.17 0.21, 1.7 27 ADL-01-0064-4 OH R═H

0.23 0.16 Not tested ADL-01-0049-5 —H —H

5.4, 3.7 0.36, 0.39 39 ADL-01-0061-0 —H —H

0.43, 0.88 0.33, 0.38 29 ADL-01-0054-5 —H —H

0.94, 0.28 0.5, 0.07, 0.06 13 ADL-01-0058-6 —H —H

0.12, 0.013 0.050, 0.060 0.009 mg/Kg (s.c.) ADL-01-0111-3 —H —H

0.30 0.12 97% @ 300 ADL-01-0123-8 —H —H

1.3 0.18 98% @ 300 ADL-01-0085-9 —H —H

22, 13 3.3, 1.3 90% A @ 300 ADL-01-0100-6 —H —H

65% @ 1 mM 98% @ 1 mM 43% @ 300 ADL-01-0122-0 —H —H

52 4.8 51% @ 300 ADL-01-0078-4 —H —H

5.4, 4.9 2.2, 1.2 Not tested ADL-01-0110-5 —H —H

75% at 1 mM 9.0 32% @ 300 ADL-01-0125-3 —H —H

19 2.2 40% @ 300 ADL-01-0146-9 —H —H

100% @ 1 mM 91% @ 1 mM 94% @ 300 ADL-01-0140-2 OH R═H

1.06 0.36 Not tested

TABLE IIIA Compounds of Formula IIIA

K_(i)(nM) [³H]- Late Phase Diprenorphin Formalin Compound X R R′ k A₅₀(mg/kg) 3a —H —H

1.0 1.8 3b —H —H

464.0 Not tested 3c —H —NHSO₂NH₂

0.12 0.27 3d —H —NHSO₂Me

0.28 16.0 3e —H —NHSO₂Me

3.2 71% @ 300 3f —H —NHSO₂Me

0.18 8.9 3g —H —NHPO₃Et₂

0.12 4.4 3h —H —NH-maleic acid

1.80 59% @ 10 3i —H —NH—C₁₀H₁₆O₄N₂

0.14 23% @ 300 3j —H —NH—C₆H₈O₃N

2.3 38% @ 300 3k —H —H

18.0 Not tested 3l —H —H

3.8 73% @ 300 3m —H —H

5.1 65% @ 300 3n —H —NHSO₂CH₃

7.3 73% @ 300 3o —H —H

30.5 59% @ 300 3p —H —H

9.7 84% @ 300 3q —H —H

3.2 Not tested 3r —H —H

7.3 10.0 3s —H —H

86% @ 300 3t —OH —H

4.2 65% @ 300 3u —H —H

1.0 48% @ 300 3v —OH —H

46.0 36% @ 300 3w —H —H

2.5 90% @ 300 3y —H —H

0.35 Not tested 3z —H —H

1.7 98% @ 300 3aa —H —H

5279.0 Not tested 3bb —H —H

438.0 Not tested 3cc —H —H

3.1 52% @ 30 3dd —H —H

3.8 65% @ 300 3ee —H —H

26.0 34% @ 300 3ff —OH —H

0.17 97% @ 300 3gg —OH —H

5.2 1.4 3hh —H —H

0.56 0.11 3ii —OH —H

0.44 88% @ 300 3jj —H —H

50% @ 1 μM Not tested 3kk —H —H

53% @ 1 μM 23% @ 300 3ll —H —H

68% @ 1 μM 77% @ 300 3mm —H —H

16.4 53% @ 300 3nn —H —H

8.8 Not tested 3oo —H —H

2.8 Not tested 3pp —H —NHSO₂CH₃

4.6 Not tested 3qq —H —NHCOCH(CH₃)₂

21.0 Not tested 3rr —H —H

0.44 2.9 3ss —H —H

361.5 Not tested 3tt —H —H

164.0 Not tested 3uu —H —OCH₃

17.5 Not tested 3vv —H —OH

19.5 Not tested 3ww —OH —H

1.28 Not tested 3xx —H —H

0.83 Not tested 3yy —H —H (R-isomer)

0% @ 1 μM Not tested 3zz —H —OCH₃

0.64 Not tested 3aaa —H —OH

0.59 Not tested 3bbb —H —H

4.45 Not tested 3ccc —H —H

1.1 Not tested 3ddd —H —H

Not tested

TABLE IV Compounds of Formula IV

Late Phase K_(i) (nM) K_(i) (nM) Formalin Compounds R diprenorphineU-69593 A₅₀ (mg) U-50488

4.3 0.6 Not tested ADL-01-0012-3 (5a)

596 100 Not tested ADL-01-0014-9 (5b)

1031 433 Not tested ADL-01-0015-6 (5c)

6.7 1.4 3.5 ADL-01-0016-4 (5d)

10.6 1.7 72.0 ADL-01-0025-5 (5e)

3185 675 Not tested ADL-01-0028-9 (5f)

14% @ 1 μM 866 Not tested ADL-01-0066-9 (5g)

77% @ 1 μM 3.75 59% @ 300 μg ADL-01-0065-1 (5h)

59% @ 1 μM 13.4 58% @ 300 μg ADL-01-0080-0 (5i)

43% @ 1 μM 5.4 73% @ 300 μg ADL-01-0118-8 (5j)

13% @ 1 μM 48% @ 1 μM Not tested ADL-01-0137-8 (5k)

16% @ 1 μM 216.0 Not tested ADL-01-0130-3 (5l)

43.5 2.35 4.7 ADL-01-0083-4 (5m)

192.5 11.25 6.2 ADL-01-0087-5 (5n)

61% @ 1 μM 10.85 70% @ 300 μg ADL-01-0088-3 (5o)

5.65 1.4 86% @ 300 μg ADL-01-0114-7 (5p)

53% @ 1 μM 25.0 Not tested ADL-01-0142-8 (5r)

50% @ 1 μM 21.0 Not tested ADL-01-0013-1 (5s)

1171 330 Not tested ADL-01-0071-9 (5t)

40% @ 1 mM 96 Not tested

TABLE IVA Compounds of Formula IVA

Formalin (% A K_(i)(nM) @ 300 μg i-paw Com- [³H]- or pounds RDiprenorphin A₅₀ (mg/kg s.c.) 4a

77.0 26% @ 300 4b

22% @ 1 μM Not tested 4c

7% @ 1 μM NT 4d

340.5 Not tested 4f

0% @ 1 μM Not tested 4g

294.0 Not tested 4h

164.0 56% @ 300 4i

31% @ 1 μM Not tested 4j (1S,2S)

10.30 91% @ 300 4k (1R,2R)

28% @ 1 μM 80% @ 300

Assessment and Testing of Anti-pruritic Activity

The formulations of the present invention for anti-pruritic activitywere tested as follows.

Testing for Anti-pruritic Activity

Testing was performed in a mouse scratch model under blind conditions.

Groups of 8-10 male Swiss albino mice (Hilltop Lab Animals, Inc.,Scottsdale, Pa.), weighing 2.5-2.6 g, were used in the testing. Theywere housed under controlled temperature of 23-25° C. Food and waterwere freely available. Before the experiments, the mice were weighed,put into individual boxes and allowed to acclimate for 30 min.

Materials

Vehicle used to dissolve the test compounds: 20% v/v cremaphor EL.

To induce scratching Compound 48/80 (Sigma, St. Louis, USA) was usedwhich has been shown to produce an itch sensation in humans (Armstronget al., J. Physiol., 120: 326, 1953).

The compounds to be tested for anti-pruritic activity were dissolved inthe vehicle of 20% v/v cremaphor EL.

Method

100 μl of the vehicle (3-5 doses, n=8-10) was injected s.c. into theback of the neck of mice 20 min before challenging them with 100 μl ofCompound 48/80 (2 mg/ml; 50 μg) injected s.c. into the back of the neck.One minute later the mice were observed for 30 min. and the number ofhindleg scratching movements directed to the neck was counted.

The vehicle-injected mice scratched 79±16 times in the 30 min after thestandard challenge with Compound 48/80.

To each mouse of a group of 8-10 mice previously subjected to thestandard challenge, various doses of the compounds to be tested foranti-pruritic activity were administered s.c. into the back of the neck.One minute later the mice were observed for 30 min and the number ofhindleg scratching movements directed to the neck was counted.

For each group of 8-10 mice, the mean values for scratching werenormalized to relative % antagonism of scratching and then plotted vs.dose of test compounds. Interval estimates of mean A₅₀ were determinedby nonlinear regression analysis (Kaleidagraph) and mean % inhibition ofscratching was calculated.

Compounds tested have shown dose-dependent anti-pruritic activity in therange of from about 15 to about 95% based on doses of from about 0.5 to10.0 mg/kg, s.c.

Formulations of the Present Invention

Effective concentrations of one or more of the compounds of the presentinvention or pharmaceutically acceptable derivatives thereof are mixedwith a suitable pharmaceutical carrier or vehicle for systemic, topicalor local administration. Compounds are included in an amount effectivefor reducing the pruritic state or other symptoms for which treatment iscontemplated. The concentration of active compound in the compositionwill depend on absorption, inactivation, excretion rates of the activecompound, the dosage schedule, and amount administered as well as otherfactors known to those of skill in the art. For topical and localadministration, the dosages are higher, typically at least about 5 to 10fold, than the amount delivered when administered systemically orally.

The compounds of the present invention possess antipruritic activity andcan be used for the relief of pruritus without loss of consciousness.

Selected compounds of the present invention have activity as narcoticantagonists. They can be used to counteract or prevent excessive centralnervous system depression and respiratory depression resulting from theadministration of morphine or other morphine-like drugs, e.g.,hydromorphone, oxymorphone, methadone and meperidine. The compounds arealso capable of inducing an abstinence syndrome in narcotic addictedsubjects, ie., induce withdrawal effects for diagnostic purposes.

The dosage of the compound of Formulas I, IA, II, IIA, III, IIIA, IV,and IVA for antipruritic purposes is from about 0.001 to about 20 mg/kgbody weight of the patient. The compounds of Formulas I, IA, II, IIA,III, IIIA, IV, and IVA are conveniently prepared in 5, 10, 25, 50, 75,100 and 200 mg dosage units for administration for 1 to 4 times a day.Preferred unit dosages are from 0.05 to 10 mg/kg body weight of thepatient.

The compounds are administered orally, parenterally, rectally andtopically.

Pharmaceutical carriers or vehicles suitable for administration of thecompounds and for the methods provided herein include any such carriersknown to those skilled in the art to be suitable for the particular modeof administration. In addition, the compounds may be formulated as thesole pharmaceutically active ingredient in the composition or may becombined with other active ingredients.

a) Systemic Formulations

The formulations of the present invention are provided foradministration to humans and animals in unit dosage forms, such astablets, capsules, pills, powders, granules, sterile parenteralsolutions or suspensions, and oral solutions or suspensions, andoil-water emulsions containing suitable quantities of a compound ofFormulas I, IA, II, IIA, III, IIIA, IV, and IVA or pharmacologicallyacceptable salts thereof.

Pharmaceutical dosage unit forms are prepared to provide from about 0.05mg to about 500 mg and preferably from about 1.0 to about 200 mg of theessential active ingredient or a combination of essential ingredientsper dosage unit form.

Oral pharmaceutical dosage forms are either solid or liquid. The soliddosage forms are tablets, capsules, granules, and bulk powders. Types oforal tablets include compressed, chewable lozenges and tablets which maybe enteric-coated, sugar-coated or film-coated. Capsules may be hard orsoft gelatin capsules, while granules and powders may be provided innon-effervescent or effervescent form with the combination of otheringredients known to those skilled in the art.

Pharmaceutically acceptable carriers utilized in tablets are binders,lubricants, diluents, disintegrating agents, coloring agents, flavoringagents, and wetting agents. Enteric-coated tablets, due to theirenteric-coating, resist the action of stomach acid and dissolve ordisintegrate in the neutral or alkaline intestines. Sugar-coated tabletsare compressed tablets to which different layers of pharmaceuticallyacceptable substances have been applied. Film-coated tablets arecompressed tablets which have been coated with a water soluble polymers.Multiple compressed tablets are compressed tablets made by more than onecompression cycle utilizing the pharmaceutically acceptable substancespreviously mentioned. Coloring agents may also be used in the abovedosage forms. Flavoring and sweetening agents are used in compressedtablets, sugar-coated, multiple compressed and chewable tablets.Flavoring and sweetening agents are especially useful in the formationof chewable tablets and lozenges.

Examples of binders include glucose solution, acacia mucilage, gelatinsolution, sucrose and starch paste. Lubricants include talc, starch,magnesium or calcium stearate, lycopodium and stearic acid. Diluentsinclude, for example, lactose, sucrose, starch, kaolin, salt, mannitoland dicalcium phosphate. Disintegrating agents include corn starch,potato starch, bentonite, methylcellulose, agar andcarboxymethylcellulose. Coloring agents include, for example, any of theapproved certified water soluble FD and C dyes, mixtures thereof andwater insoluble FD and C dyes suspended on alumia hydrate. Sweeteningagents include sucrose, lactose, mannitol and artificial sweeteningagents such as sodium cyclamate and saccharin, and any number of spraydried flavors. Flavoring agents include natural flavors extracted fromplants such as fruits and synthetic blends of compounds which produce apleasant sensation. Wetting agents include propylene glycolmonostearate, sorbitan monooleate, diethylene glycol monolaurate andpolyoxyethylene laural ether. Enteric-coatings coatings include fattyacids, fats, waxes, shellac, ammoniated shellac and cellulose acetatephthalates. Film coatings include hydroxyethylcellulose, sodiumcarboxymethylcellulose, polyethylene glycol 4000 and cellulose acetatephthalate.

Liquid oral dosage forms include aqueous solutions, emulsions,suspensions, solutions and/or suspensions reconstituted fromnon-effervescent granules and effervescent preparations reconstitutedfrom effervescent granules. Aqueous solutions include, for example,elixirs and syrups. Emulsions are either oil-in water or water-in-oil.

Elixirs are clear, sweetened, hydroalcoholic preparations.Pharmaceutically acceptable carriers used in elixirs include solvents.Syrups are concentrated aqueous solutions of a sugar, for example,sucrose, and may contain a preservative. An emulsion is a two-phasesystem in which one liquid is dispersed in the form of small globulesthroughout another liquid. Pharmaceutically acceptable carriers used inemulsions are non-aqueous liquids, emulsifying agents and preservatives.Suspensions use pharmaceutically acceptable suspending agents andpreservatives. Pharmaceutically acceptable substances used innon-effervescent granules, to be reconstituted into a liquid oral dosageform, include diluents, sweeteners and wetting agents. Pharmaceuticallyacceptable substance used in effervescent granules, to be reconstitutedinto a liquid oral dosage form, include organic acids and a source ofcarbon dioxide. Coloring and flavoring agents are used in all of theabove dosage forms.

Solvents include glycerin, sorbitol, ethyl alcohol and syrup. Examplesof preservatives include glycerin, methyl and propylparaben, benzoicacid, sodium benzoate and alcohol. Examples of non-aqueous liquidsutilized in emulsions include mineral oil and cottonseed oil. Examplesof emulsifying agents include gelatin, acacia, tragacanth, bentonite,and surfactants such as polyoxyethylene sorbitan monooleate. Suspendingagents include sodium carboxymethylcellulose, pectin, tragacanth, Veegumand acacia. Diluents include lactose and sucrose. Sweetening agentsinclude sucrose, syrups, glycerin and artificial sweetening agents suchas sodium cyclamate and saccharin. Wetting agents include propyleneglycol monostearate, sorbitan monooleate, diethylene glycol monolaurateand polyoxyethylene lauryl ether. Organic acids include citric andtartaric acid. Sources of carbon dioxide include sodium bicarbonate andsodium carbonate. Coloring agents include any of the approved certifiedwater soluble FD and C dyes, and mixtures thereof. Flavoring agentsinclude natural flavors extracted from plants such fruits, and syntheticblends of compounds which produce a pleasant taste sensation.

Parenteral administration of the formulations of the present inventionincludes intravenous, subcutaneous and intramuscular administrations.

Preparations for parenteral administration include sterile solutionsready for injection, sterile dry soluble products ready to be combinedwith a solvent just prior to use, including hypodermic tablets, sterilesuspensions ready for injection, sterile dry insoluble products ready tobe combined with a vehicle just prior to use and sterile emulsions. Thesolutions may be either aqueous or nonaqueous.

Pharmaceutically acceptable carriers used in parenteral preparationsinclude aqueous vehicles, nonaqueous vehicles, antimicrobial agents,isotonic agents, buffers, antioxidants, local anesthetics, suspendingand dispersing agents, emulsifying agents, sequestering or chelatingagents and other pharmaceutically acceptable substances.

Examples of aqueous vehicles include Sodium Chloride Injection, RingersInjection, Isotonic Dextrose Injection, Sterile Water Injection,Dextrose and Lactated Ringers Injection. Nonaqueous parenteral vehiclesinclude fixed oils of vegetable origin, cottonseed oil, corn oil, sesameoil and peanut oil. Antimicrobial agents in bacteriostatic orfungistatic concentrations must be added to parenteral preparationspackaged in multiple-dose containers which include phenols or cresols,mercurials, benzyl alcohol, chlorobutanol, methyl and propylp-hydroxybenzoic acid esters, thimerosal, benzalkonium chloride andbenzethonium chloride. Isotonic agents include sodium chloride anddextrose. Buffers include phosphate and citrate. Antioxidants includesodium bisulfate. Local anesthetics include procaine hydrochloride.Suspending and dispersing agents include sodium carboxymethylcelluose,hydroxypropyl methylcellulose and polyvinylpyrrolidone. Emulsifyingagents include Polysorbate 80 (Tween 80). A sequestering or chelatingagent of metal ions include EDTA. Pharmaceutical carriers also includeethyl alcohol, polyethylene glycol and propylene glycol for watermiscible vehicles and sodium hydroxide, hydrochloric acid, citric acidor lactic acid for pH adjustment.

The concentration of the pharmaceutically active compound is adjusted sothat an injection provides an effective amount to produce the desiredpharmacological effect. The exact dose depends on the age, weight andcondition of the patient or animal as is known in the art.

The unit-dose parenteral preparations are packaged in an ampoule or asyringe with a needle.

All preparations for parenteral administration must be sterile, as isknown and practiced in the art.

Illustratively, intravenous or intraarterial infusion of a sterileaqueous solution containing an active compound is an effective mode ofadministration. Another embodiment is a sterile aqueous or oily solutionor suspension containing an active material injected as necessary toproduce the desired pharmacological effect.

Pharmaceutical dosage forms for rectal administration are rectalsuppositories, capsules and tablets for systemic effect.

Rectal suppositories are used herein mean solid bodies for insertioninto the rectum which melt or soften at body temperature releasing oneor more pharmacologically or therapeutically active ingredients.

Pharmaceutically acceptable substances utilized in rectal suppositoriesare bases or vehicles and agents to raise the melting point.

Examples of bases include cocoa butter (theobroma oil),glycerin-gelatin, carbowax, (polyoxyethylene glycol) and appropriatemixtures of mono-, di- and triglycerides of fatty acids. Combinations ofthe various bases may be used. Agents to raise the melting point ofsuppositories include spermaceti and wax. Rectal suppositories may beprepared either by the compressed method or by molding. The typicalweight of a rectal suppository is about 2 to 3 gm.

Tablets and capsules for rectal administration are manufactured usingthe same pharmaceutically acceptable substance and by the same methodsas for formulations for oral administration.

The pharmaceutically therapeutically active compounds of Formulas I, II,III and IV are administered orally, parenterally or rectally inunit-dosage forms or multiple-dosage forms. Unit-dose forms as usedherein refers to physically discrete units suitable for human and animalsubjects and packaged individually as is known in the art. Eachunit-dose contains a predetermined quantity of the therapeuticallyactive compound sufficient to produce the desired therapeutic effect, inassociation with the required pharmaceutical carrier, vehicle ordiluent. Examples of unit-dose forms include ampoules and syringesindividually packaged tablet or capsule. Unit-dose forms may beadministered in fractions or multiples thereof. A multiple-dose form isa plurality of identical unit-dosage forms packaged in a singlecontainer to be administered in segregated unit-dose form. Examples ofmultiple-dose forms include vials, bottles of tablets or capsules orbottles of pint or gallons. Hence, multiple dose form is a multiple ofunit-doses which are not segregated in packaging.

Compounds of the present invention in formulations may be included withother active compounds to obtain desired combinations of properties.Other active compounds with known pharmacological properties includeanalgesics such as aspirin, phenacetin acetaminophen, propoxyphene,pentazocine, codeine, meperidine, oxycodone, mefenamic acid, andibuprofen; muscle relaxants such as methocarbamol, orphenadrine,carisoprodol, meprobamate, chlorphenesin carbamate, diazepam,chlordiazepoxide and chlorzoxazone; analeptics such as caffeine,methylphenidate and pentylenetetrazol; corticosteroids such asmethylprednisolone, prednisone, prednisolone and dexamethasone;antihistmines such as chlorpheniramine, cyproheptadine, promethazine andpyrilamine.

b) Local and Topical Formulations

Typically a therapeutically effective dosage is formulated to contain aconcentration of at least about 0.1% w/w up to about 50% w/w or more,preferably more than 1% w/w of the active compound to the treatedtissue. The active ingredient may be administered at once, or may bedivided into a number of smaller doses to be administered at intervalsof time. It is understood that the precise dosage and duration oftreatment is a function of the tissue being treated and may bedetermined empirically using known testing protocols or by extrapolationfrom in vivo or in vitro test data. It is to be noted thatconcentrations and dosage values may also vary with the age of theindividual treated. It is to be further understood that for anyparticular subject, specific dosage regimens should be adjusted overtime according to the individual need and the professional judgment ofthe person administering or supervising the administration of theformulations, and that the concentration ranges set forth herein areexemplary only and are not intended to limit the scope or practice ofthe claimed formulations.

The compound may be suspended in micronized or other suitable form ormay be derivatized to produce a more soluble active product or toproduce a prodrug. The form of the resulting mixture depends upon anumber of factors, including the intended mode of administration and thesolubility of the compound in the selected carrier or vehicle. Theeffective concentration is sufficient for ameliorating the hyperalgesicor other condition and may be empirically determined.

Compounds are typically included at concentrations 0.001% w/w or greaterthan 1% w/w up to 50% w/w or higher. The concentration is generallygreater than the concentration for systemic administration of thecompound. Preferable concentrations are in the range of 0.01% w/w toabout 25%w/w, more preferably 1% w/w to 25% w/w, yet more preferablygreater than about 1% w/w to about 10% w/w, and most preferably greaterthan 1% w/w up to about 5% w/w. Aqueous suspensions and formulationscontain 1% w/w or more.

The resulting mixture may be a solution, suspension, emulsions or thelike and are formulated as creams, gels, ointments, emulsions,solutions, elixirs, lotions, suspensions, tinctures, pastes, foams,aerosols, irrigations, sprays, suppositories, bandages, or any otherformulations suitable for topical or local administration.

The route of administration herein is topical or local administration,and compositions are formulated in a manner suitable for each route ofadmiration. Preferred modes of administration include topicalapplication to the skin, eyes or mucosa, and local application to thejoints, such as by intra-articular injection. Thus, typical vehicles arethose suitable for pharmaceutical or cosmetic application to bodysurfaces or for local injection.

Pharmaceutical and cosmetic carriers or vehicles suitable foradministration of the compounds provided herein include any suchcarriers known to those skilled in the art to be suitable for theparticular mode of administration. In addition, the compounds may beformulated as the sole pharmaceutically active ingredient in thecomposition or may be combined with other active ingredients. The activecompound is included in the carrier in an amount sufficient to exert atherapeutically useful effect in the absence of serious toxic effects onthe treated individual. The effective concentration may be determinedempirically by testing the compounds using in vitro and in vivo systems,including the animal models described herein.

For topical administration, the compounds may be formulated incompositions in the form of gels, creams, lotions, solids, solutions orsuspensions, or aerosols. Compositions for treating human skin areformulated for topical application with an anti-hyperalgesic effectiveamount of one or more of the compounds selected as described herein, inan effective concentration range [by weight], between about 0.1% and80%, preferably 0.1 to 500/%, more preferably greater than about 1% upto about 50% or more in a cream, ointment, lotion, gel, solution orsolid base or vehicle known in the art to be non-toxic anddermatologically acceptable or suitable for application to the mucosa.Aqueous suspensions are preferably formulated at concentrations greaterthan about 1% w/w, more preferably 2% w/w.

To formulate a composition, the weight fraction of compound isdissolved, suspended, dispersed or otherwise mixed in a selected vehicleat an effective concentration such that the hyperalgesic condition isrelieved or ameliorated. Generally, emollient or lubricating vehiclesthat help hydrate the skin are more preferred than volatile vehicles,such as ethanol, that dry the skin. Examples of suitable bases orvehicles for preparing compositions for use with human skin arepetrolatum, petrolatum plus volatile silicones, lanolin, cold cream[USP], and hydrophilic ointment [USP].

The choice of an acceptable vehicle is largely determined by the mode ofapplication and tissue to be treated. Suitable pharmaceutically anddermatologically acceptable vehicles for topical application includethose suited for use include lotions, creams, solutions, gels, tapes andthe like. Generally, the vehicle is either organic in nature or anaqueous emulsion and capable of having the selected compound orcompounds, which may be micronized, dispersed, suspended or dissolvedtherein. The vehicle may include pharmaceutically-acceptable emollients,skin penetration enhancers, coloring agents, trances, emulsifiers,thickening agents, and solvents.

For local internal administration, such as intra-articularadministration, the compounds are preferably formulated as a suspensionin an aqueous-based medium, such as isotonically buffered saline or arecombined with a biocompatible support or bioadhesive intended forinternal administration.

Lotions

The lotions contain an effective concentration of one or more of thecompounds. The effective concatenation is preferably effective todeliver an anti-hyperalgesic amount, typically at a concentration ofbetween about 0.1-50% w/w or more of one or more of the compoundsprovided herein. The lotions also contain from 1% to 50% w/w, preferablyfrom 3% to 15% w/w of an emollient and the balance water, a suitablebuffer, a C2 or C3 alcohol, or a mixture of water of the buffer and thealcohol. Any emollients known to those of skill in the art as suitablefor application to human skin may be used. These include, but are notlimited to, the following:

(a) Hydrocarbon oils and waxed, including mineral oil, petrolatum,paraffin, ceresin, ozokerite, microcrystalline wax, polyethylene, andperhydrosqualene.

(b) Silicone oils, including dimethylpolysiloxanes,methylphenylpolysiloxanes, water-soluble and alcohol-solublesilicone-glycol copolymers.

(c) Triglyceride fats and oils, including those derived from vegetable,animal and marine sources. Examples include, but are not limited to,castor oil safflower oil, cotton seed oil, corn oil, olive oil, codliver oil, almond oil, avocado oil, palm oil, sesame oil and soybeanoil.

(d) Acetoglyceride esters, such as acetylated monoglycerides.

(e) Ethoxylated glycerides, such as ethoxylated glyceryl monostearate.

(f) Alkyl esters of fatty acids having 10 to 20 carbon atoms. Methylisopropyl and butyl esters of fatty acids are useful herein. Examplesinclude, but are not limited to, hexyl laurate, isohexyl laurate,isohexyl palmitate, isopropyl palmitate, isopropyl myristate, decyloleate, isodecyl oleate, hexadecyl stearate, decyl stearate, isopropylisostearate diisopropyl adipate, diisohexyl adipate, dihexyldecyladipate, diisopropyl sebacate, lauryl lactate, myristyl lactate, andcetyl lactate.

(g) Alkenyl esters of fatty acids having 10 to 20 carbon atoms. Examplesthereof include, but are not limited to, oleyl myristate, oleylstearate, and oleyl oleate.

(h) Fatty acids having 9 to 22 carbon atoms. Suitable examples include,but are not limited to pelargonic, lauric, myristic, palmitic, stearic,isostearic, hydroxystearic, oleic, linoleic, ricinoleic, arachidonic,behenic, and erucic acids.

(i) Fatty alcohols having 10 to 20 carbon atoms, such as but not limitedto, lauryl myristyl cetyl hexadecyl, stearyl isostearyl, hydroxystearyl,oleyl, ricinoleyl behenyl erucyl and 2-octyl dodecyl alcohols.

(j) Fatty alcohol ethers, including, but not limited to, ethoxylatedfatty alcohols of 10 to 20 carbon atoms, such as, but are not limitedto, the lauryl cetyl, stearyl, isostearyl, oleyl and cholesterolalcohols having attached thereto from 1 to 50 ethylene oxide groups or 1to 50 propylene oxide groups or mixtures thereof

(k) Ether-esters, such as fatty acid esters of ethoxylated fattyalcohols.

(l) Lanolin and derivatives, including but not limited to, lanolin,lanolin oil, lanolin wax, lanolin alcohols, lanolin fatty acids,isopropyl lanolate, ethoxylated lanolin, ethoxylated lanolin alcohols,ethoxylated cholesterol propoxylated lanolin alcohols, acetylatedlanolin, acetylated lanolin alcohols, lanolin alcohols linoleate,lanolin alcohols ricinoleate, acetate of lanolin alcohols ricinoleate,acetate of ethoxylated alcohols-esters, hydrogenolysis of lanolin,ethoxylated hydrogenated lanolin, ethoxylated sorbitol lanolin, andliquid and semisolid lanolin absorption bases.

(m) Polyhydric alcohols and polyether derivatives, including, but notlimited to, propylene glycol, dipropylene glycol, polypropylene glycol[M.W. 2000-4000], polyoxyethylene polyoxypropylene glycols,polyoxypropylene polyoxyethylene glycols, glycerol, ethoxylatedglycerol, propoxylated glycerol, sorbitol, ethoxylated sorbitol,hydroxypropyl sorbitol, polyethylene glycol [M.W. 200-6000], methoxypolyethylene glycols 350, 550, 750, 2000, 5000, poly)ethylene oxide)homopolymers [M.W. 100,000-5,000,000], polyalkylene glycols andderivatives, hexylene glycol (2-methyl-2,4-pentanediol), 1,3-butyleneglycol, 1,2,6hexanetriol, ethohexadiol USP (2-ethyl-1,3-hexanediol),C₁₅-C₁₈ vicinal glycol and polyoxypropylene derivatives oftrimethylolpropane.

(n) Polyhydric alcohol esters, including, but not limited to, ethyleneglycol mono- and di-fatty acid esters, diethylene glycol mono- anddi-fatty acid esters, polyethylene glycol [M.W. 200-6000], mono- anddi-fatty esters, propylene glycol mono- and di-fatty acid esters,polypropylene glycol 2000 monooleate, polypropylene glycol 2000monostearate, ethoxylated propylene glycol monostearate, glyceryl mono-and di-fatty acid esters, polyglycerol poly-fatty acid esters,ethoxylated glyceryl monostearate, 1,3-butylene glycol monostearate,1,3-butylene glycol distearate, polyoxyethylene polyol fatty acid ester,sorbitan fatty acid esters, and polyoxyethylene sorbitan fatty acidesters.

(o) Wax esters, including, but not limited to, beeswax, spermacetimyristyl myristate, and stearyl stearate and beeswax derivatives,including, but not limited to, polyoxyethylene sorbitol beeswax, whichare reaction products of beeswax with ethoxylated sorbitol of varyingethylene oxide content that form a mixture of ether-esters.

(p) Vegetable waxes, including, but not limited to, carnauba andcandelilla waxes.

(q) Phospholipids, such as lecithin and derivatives.

(r) Sterols, including, but not limited to, cholesterol and cholesterolfatty acid esters.

(s) Amides, such as fatty acid amides, ethoxylated fatty acid amides,and solid fatty acid alkanolamides.

The lotions further preferably contain from 1% w/w to 10% w/w, morepreferably from 2% w/w to 5% w/w, of an emulsifier. The emulsifiers canbe nonionic, anionic or cationic. Examples of satisfactory nonionicemulsifiers include, but are not limited to, fatty alcohols having 10 to20 carbon atoms, fatty alcohols having 10 to 20 carbon atoms condensedwith 2 to 20 moles of ethylene oxide or propylene oxide, alkyl phenolswith 6 to 12 carbon atoms in the alkyl chain condensed with 2 to 20moles of ethylene oxide, mono- and di-fatty acid esters of ethyleneoxides mono- and di-fatty acid esters of ethylene glycol wherein thefatty acid moiety contains from 10 to 20 carbon atoms, diethyleneglycol, polyethylene glycols of molecular weight 200 to 6000, propyleneglycols of molecular weight 200 to 3000, glycerol, sorbitol, sorbitan,polyoxyethylene sorbitol, polyoxyethylene sorbitan and hydrophilic waxesters. Suitable anionic emulsifiers include, but are not limited to,the fatty acid soaps, e.g. sodium potassium and triethanolamine soaps,wherein the fatty acid moiety contains from 10 to 20 carbon atoms. Othersuitable anionic emulsifiers include, but are not limited to, the alkalimetal, ammonium or substituted ammonium alkyl sulfates, alkylarylsulfonates, and alkyl ethoxy ether sulfonates having 10 to 30 carbonatoms in the alkyl moiety. The alkyl ethoxy ether sulfonates containfrom 1 to 50 ethylene oxide units. Among satisfactory cationicemulsifiers are quaternary ammonium, morpholinium and pyridiniumcompounds. Certain of the emollients described in preceding paragraphsalso have emulsifying properties. When a lotion is formulated containingsuch an emollient, an additional emulsifier is not needed, though it canbe included in the composition

The balance of the lotion is water or a C₂ or C₃ alcohol, or a mixtureof water and the alcohol. The lotions are formulated by simply admixingall of the components together. Preferably, the compound, is dissolved,suspended or otherwise uniformly dispersed in the mixture.

Other conventional components of such lotions may be included. One suchadditive is a thickening agent at a level from 1% to 10% w/w of thecomposition. Examples of suitable thickening agents include, but are notlimited to: cross-linked carboxypolymethylene polymers, ethyl cellulose,polyethylene glycols, gum, tragacanth, gum kharaya, xanthan gums andbentonite, hydroxyethyl cellulose, and hydroxypropyl cellulose.

Creams

The creams are formulated to contain concentration effective to deliveran anti-pruritic effective amount of the compound to the treated tissue,typically at between about 0.1%, preferably at greater than 1% up to andgreater than 50%, preferably between about 3% and 50%, more preferablybetween about 5% and 15% of one or more of the compounds providedherein. The creams also contain from 5% to 50%, preferably from 10% to25%, of an emollient and the remainder is water or other suitablenon-toxic carrier, such as an isotonic buffer. The emollients, asdescribed above for the lotions, can also be used in the creamcompositions. The cream may also contain a suitable emulsifier, asdescribed above. The emulsifier is included in the composition at alevel from 3% to 50%, preferably from 5% to 20%.

Solutions and Suspensions for Topical and Local Administration

The solutions are formulated to contain an amount of one or morecompounds effective to deliver an anti-pruritic amount, typically at aconcentration of between about 0.1-50% w/w, preferably at least morethan 1% w/w, more preferably more than 2% w/w of one or more of thecompounds provided herein. The balance is water, a suitable organicsolvent or other suitable solvent or buffer. Suitable organic materialsuseful as the solvent or a part of a solvent system are as follows:propylene glycol, polyethylene glycol [M.W. 200-600], polypropyleneglycol [M.W. 425-2025], glycerine, sorbitol esters, 1,2,6-hexanetriol,ethanol, isopropanol, diethyl tartrate, butanediol and mixtures thereof.Such solvent systems can also contain water.

Solutions or suspensions used for local application can include any ofthe following components: a sterile diluent, such as water forinjection, saline solution, fixed oil, polyethylene glycol, glycerine,propylene glycol or other synthetic solvent; antimicrobial agents, suchas benzyl alcohol and methyl parabens; antioxidants, such as ascorbicacid and sodium bisulfite; chelating agnets, such asethylenediaminetetraacetic acid [EDTA]; buffers, such as acetates,citrates and phosphates; and agents for the adjustment of tonicity suchas sodium chloride or dextrose. Liquid preparations can be enclosed inampoules, disposable syringes or multiple dose vials made of glass,plastic or other suitable material. Suitable carriers may includephysiological saline or phosphate buffered saline [PBS], and thesuspensions and solutions may contain thickening and solubilizingagents, such as glucose, polyethylene glycol, and polypropylene glycoland mixtures thereof. Liposomal suspensions, may also be suitable aspharmaceutically acceptable carriers. These may be prepared according tomethods known to those skilled in the art.

These compositions that are formulated as solutions or suspensions maybe applied to the skin, or may be formulated as an aerosol or foam andapplied to the skin as a spray-on. The aerosol compositions typicallycontain from 25% to 80% w/w, preferably from 30% to 50% w/w, of asuitable propellant. Examples of such propellants are the chlorinated,fluorinated and chlorofluorinated lower molecular weight hydrocarbons.Nitrous oxide, carbon dioxide, butane, and propane are also used aspropellant gases. These propellants are used as understood in the art ina quantity and under a pressure suitable to expel the contents of thecontainer.

Suitably prepared solutions and suspension may also be topically appliedto the eyes and mucosa. Solutions, particularly those intended foropthalmic use, may be formulated as 0.01%-10% w/w isotonic solutions, pHabout 5-7, with appropriate salts, and preferably containing one or moreof the compounds herein at a concentration of about 0.1% w/w known [see,e.g U.S. Pat. No. 5,116,868, which describes typical compositions ofopthalmic irrigation solutions and solutions for topical application].Such solutions, which have a pH adjusted to about 7.4, contain, forexample, 90-100 mM sodium chloride, 4-6 mM dibasic potassium phosphate,4-6 mM dibasic sodium phosphate, 8-12 mM sodium citrate, 0.5-1.5 mMmagnesium chloride, 1.5-2.5 mM calcium chloride, 15-25 mM sodiumacetate, 10-20 mM D.L.-sodium β-hydroxybutyrate and 5-5.5 mM glucose.

The active compounds of the present invention can also be mixed withother active materials, that do not impair the desired action, or withmaterials that supplement the desired action, including viscoelasticmaterials, such as hyaluronic acid, which is sold under the trademarkHEALON [solution of a high molecular weight (MW of about 3 million)fraction of sodium hyaluronate; manufactured by Pharmacia, Inc. see,e.g., U.S. Pat. Nos. 5,292,362, 5,282,851, 5,273,056, 5,229,127,4,517,295 and 4,328,803], VISCOAT [fluorine-containing (meth) acrylates,such as, 1H, 2H, 2H-heptadecafluorodecylmethacrylate; see, e.g. , U.S.Pat. Nos. 5,278,126, 5,273,751 and 5,214,080; commercially availablefrom Alcon Surgical, Ic.], ORCOLON [see, e.g., U.S. Pat. Nos. 5,273,056;commercially available from Optical Radiation Corporation],methylcellulose, methyl hyaluronate, polyacrylamide andpolymethacrylamide [see, e.g., U.S. Pat. No. 5,273,751]. Theviscoelastic materials are present generally in amounts ranging fromabout 0.5 to 5.0% w/w, preferably 1 to 3% w/w of the conjugate materialand serve to coat and protect the treated tissues. The compositions mayalso include a dye, such as methylene blue or other inert dye, so thatthe composition can be seen when injected into the eye or contacted withthe surgical site during surgery.

Gels

Gel compositions can be formulated by simply admixing a suitablethickening agent to the previously described solution or suspensioncomposition. Examples of suitable thickening agents have been previouslydescribed with respect to the lotions.

The gelled compositions contain an effective amount of one or more of ananti-pruritic amount, typically at a concentration of between about0.1-50% w/w or more of one or more of the compounds provided therein;from 5% to 75% w/w, preferably from 10% to 50% w/w, of an organicsolvent as previously described; from 0.5% to 20% w/w, preferably from1% to 10% w/w of the thickening agent; the balance being water or otheraqueous carrier.

Solids

Compositions of solid forms may be formulated as stick-type compositionsintended for application to the lips or other parts of the body. Suchcompositions contain an effective amount of one or more of the compoundsprovided therein. The amount is typically an amount effective to deliveran anti-pruritic amount, typically at a concentration of between about0.1-50% w/w or more of one or more of the compounds provided herein. Thesolids also contain from about 40% to 98% w/w, preferably from about 50%to 905 w/w, of the previously described emollients. This composition canfurther contain from 1% to 20% w/w, preferably from 5% to 15% w/w, of asuitable thickening agent, and, if desired or needed, emulsifiers andwater or buffers. Thickening agents previously described with respect tolotions are suitably employed in the composition in solid form.

Other ingredients such as preservatives, including methyl-paraben orethyl-paraben, perfumes, dyes or the like, that are known in the art toprovide desirable stability, fragrance or color, or other desirableproperties, such as shielding from actinic rays from the sun, tocompositions for application to the skin may also be employed in acomposition for such topical application.

Additional Ingredients

Other active ingredients include, but are not limited to, antibiotics,antivirals, antifungals, anti-inflammatories, including steroidal andnon-steroidal anti-inflammatories, anesthetics and mixtures thereof.Such additional ingredients include any of the following:

a. Antibacterial Agents

Aminoglycosides, such as Amikacin, Apramycin, Arbekacin, Bambermycins,Butirosin, Dibekacin, Dihydrostreptomycin, Fortimicin(s), Fradiomycin,Gentamicin, Ispamicin, Kanamycin, Micronomicin, Neomycin, NeomycinUndecylenate, Netilmicin, Paromomycin, Ribostamycin, Sisomicin,Spectinomycin, Streptomycin, Streptonicozid and Tobramycin;

Amphenicols, such as Azidamfenicol, Chloramphenicol, ChloramphenicolPalmirate, Chloramphenicol Pantothenate, Florfenicol, Thiamphenicol;

Ansamycins, such as Rifamide, Rifampin, Rifamycin and Rifaximin;

β-Lactams;

Carbapenems, such as Imipenem;

Cephalosporins, such as 1-Carba (dethia) Cephalosporin, Cefactor,Cefidroxil, Cefamandole, Cefatrizine, Cefazedone, Cefazolin, Cefixime,Cefmenoxime, Cefodizime, Cefonicid, Cefoperazone, Ceforanide,Cefotaxime, Cefotiam, Cefpimizole, Cefpirimide, Cefpodoxime Proxetil,Cefroxadine, Cefsulodin, Ceftazidime, Cefteram, Ceflezole, Ceftibuten,Ceftizoxime, Ceftriaxone, Cefuroxime, Cefizonam, Cephacetrile Sodium,Cephalexin, Cephaloglycin, Cephaloridine, Cephalosporin, Cephalothin,Cephapirin Sodium, Cephradine and Pivcefalexin;

Cephamycins such as Cefbuperazone, Cefinetazole, Cefmininox, Cefetan andCefoxitin;

Monobactams such as Aztreonam, Canumonam and Tigemonan;

Oxacephems such as Flomoxef and Moxolactam;

Penicillins such as Amidinocillin, Amdinocillin, Pivoxil, Amoxicillin,Ampicillan, Apalcillin, Aspoxicillin, Azidocillan, Azlocillan,Bacampicillin, Benzylpenicillinic Acid, Benzylpenicillin, Carbenicillin,Carfecillin, Carindacillin, Clometocillin, Cloxacillin, Cyclacillin,Dicloxacillin, Diphenicillin, Epicillin, Fenbenicillin, Floxicillin,Hetacillin, Lenampicillin, Metampicillin, Methicillin, Meziocillin,Nafcillin, Oxacillin, Penamecillin, Penethamate Hydriodide, Penicillin GBenethamine, Penicillin G Benzathine, Penicillin G Benzhydrylamine,Penicillin G Calcium, Penicillin G Hydragamine, Penicillin G Potassium,Penicillin G. Procaine, Penicillin N, Penicillin O, Penicillin V,Penicillin V Benzathine, Penicillin V Hydrabamine, Penimepicycline,Phenethicillin, Piperacillin, Pivapicillin, Propicillin, Quinacillin,Sulbenicillin, Talampicillin, Temocillin and Ticarcillin;

Lincosamides such as Clindamycin and Lincomycin;

Macrolides such as Azithromycin, Carbomycin, Clarithromycin,Erythromycin(s) and Derivatives, Josamycin, Leucomycins, Midecamycins,Miokamycin, Oleandomycin, Primycin, Rokitamycin, Rosaramicin,Roxithromycin, Spiramycin and Troleandomycin;

Polypeptides such as Amphomycin, Bacitracin, Capreomycin, Colistin,Enduracidin, Enviomycin, Fusafungine, Gramicidin(s), Gramicidin S,Mikamycin, Polymyxin, Polymyxin β-Methanesulfonic Acid, Pristinamycin,Ristocetin, Teicoplanin, Thiostrepton, Tuberactinomycin, Tyrocidine,Tyrothricin, Vancomycin, Viomycin(s), Virginiamycin and Zinc Bacitracin;

Tetracyclines such as Spicycline, Chlortetracycline, Clomocycline,Demeclocycline, Doxycycline, Guamecycline, Lymecycline, Meclocycline,Methacycline, Minocycline, Oxytetracycline, Penimepicycline,Pipacycline, Rolitetracycline, Sancycline, Senociclin and Tetracycline;and

others such as Cycloserine, Mupirocin, Tuberin.

b. Synthetic Antibacterials

2,4-Diaminopyrimidines such as Brodimoprim, Tetroxoprin andTrimethoprim;

Nitrofurans such as Furaltadone, Furazolium, Nifuradene, Nifuratel,Nifurfoline, Nifurpirinol, Nifurprazine, Nifurtoinol and Nitrofurantoin;

Quinolones and analogs thereof such as Amifloxacin, Cinoxacin,Ciprofloxacin, Difloxacin, Enoxacin, Fleroxacin, Flumequine,Lomefloxacin, Miloxacin, Nalidixic Acid, Norfloxacin, Ofloxacin,Oxolinic Acid, Perfloxacin, Pipemidic Acid, Piromidic Acid, Rosoxacin,Temafloxacin and Tosufloxacin;

Sulfonamides such as Acetyl Sulfamethoxypyrazine, Acetyl Sulfisoxazole,Azosulfamide, Benzylsulfamide, Chloramine-β, Chloramine-T,Dichloramine-T, Formosulfathiazole, N²-Formyl-sulfisomidine,N⁴-β-D-Glucosylsulfanilamide, Mafenide,4′-(Methyl-sulfamoyl)sulfanilanilide, p-Nitrosulfathiazole,Noprylsulfamide, Phthalylsulfacetamide, Phthalylsulfathiazole,Salazosulfadimidine, Succinylsulfathiazole, Sulfabenzamide,Sulfacetamide, Sulfachlorpyridazine, Sulfachrysoidine, Sulfacytine,Sulfadiazine, Sulfadicramide, Sulfadimethoxine, Sulfadoxine,Sulfaethidole, Sulfaguanidine, Sulfaguanol, Sulfalene, Sulfaloxic Acid,Sulfamerazine, Sulfameter, Sulfamethazine, Sulfamethizole,Sulfamethomidine, Sulfamethoxazole, Sulfamethoxypyridazine,Sulfametrole, sulfamidochrysoidine, Sulfamoxole, Sulfanilamide,Sulfanilamidomethanesulfonic Acid Triethanolamine Salt,4-Sulfanilamidosalicyclic Acid, N⁴-Sulfanilylsulfanilamide,Sulfanilylurea, N-Sulfanilyl-3,4-xylamide, Sulfanitran, Sulfaperine,Sulfaphenazole, Sulfaproxyline, Sulfapyrazine, Sulfapyridine,Sulfasomizole, Sulfasymazine, Sulfathiazole, Sulfathiourea,Sulfatolamide, Sulfisomidine and Sulfisoxazole;

Sulfones, such as Acedapsone, Acediasulfone, Acetosulfone, Dapsone,Diathymosulfone, Glucosulfone, Solasulfone, Succisulfone, SulfanilicAcid, p-Sulfanilylbenzylamine, p,p′-sulfonyldianiline-N,N′digalactoside,Sulfoxone and Thiazolsulfone;

Others such as Clofoctol, Hexedine, Magainins, Methenamine, MethenamineAnhydromethylene-citrate, Methenamine Hippurate, Methenamine Mandelate,Methenamine Sulfosalicylate, Nitroxoline, Squalamine and Xibornol.

C. Antifungal (Antibiotics)

Polyenes such as Amphotericin-B, Candicidin, Dermostatin, Filipin,Fungichromin, Hachimycin, Hamycin, Lucensomycin, Mepartricin, Natamycin,Nystatin, Pecilocin, Perimycin; and others, such as Azaserine,Griseofulvin, Oligomycins, Pyrrolnitrin, Siccanin, Tubercidin andViridin.

d. Antifungal (Synthetic)

Allylamines such as Naftifine and terbinafine;

Imidazoles such as Bifonazole, Butoconazole, Chlordantoin,Chlormidazole, Cloconazole, Clotrimazole, Econazole, Enilconazole,Finticonazole, Isoconazole, Ketoconazole, Miconazole, Omoconazole,Oxiconazole Nitrate, Sulconazole and Tioconazole;

Triazoles such as Fluconazole, Itraconazole, Terconazole;

Others such as Acrisorcin, Amorolfine, Biphenamine,Bromosalicylchloranilide, Buclosamide, Chlophenesin, Ciclopirox,Cloxyquin, Coparaffinate, Diamthazole, Dihydrochloride, Exalamide,Flucytosine, Halethazole, Hexetidine, Loflucarban, Nifuratel, PotassiumIodide, Propionic Acid, Pyrithione, Salicylanilide, Sulbentine,Tenonitrozole, Tolciclate, Tolindate, Tolnaftate, Tricetin, Ujothion,and Undecylenic Acid.

e. Antiglaucoma Agents

Antiglaucoma agents, such as Dapiprazoke, Dichlorphenamide, Dipivefrinand Pilocarpine.

f. Anti-inflammatory Agents

Corticosteroids, aminoarylcarboxylic Acid Derivatives such asEtofenamate, Meclofenamic Acid, Mefanamic Acid, Niflumic Acid;

Arylacetic Acid Derivatives such as Acemetacin, Amfenac Cinmetacin,Clopirac, Diclofenac, Fenclofenac, Fenclorac, Fenclozic Acid, Fentiazac,Glucametacin, Isozepac, Lonazolac, Metiazinic Acid, Oxametacine,Proglumetacin, Sulindac, Tiaramide and Tolmetin;

Arylbutyric Acid Derivatives such as Butibufen and Fenbufen;

Arylcarboxylic Acids such as Clidanac, Ketorolac and Tinoridine;

Arylpropionic Acid Derivatives such as Bucloxic Acid, Carprofen,Fenoprofen, Flunoxaprofen, Ibuprofen, Ibuproxam, Oxaprozin,Piketoprofen, Pirprofen, Pranoprofen, Protizinic Acid and TiaprofenicAcid;

Pyrazoles such as Mepirizole;

Pyrazolones such as Clofezone, Feprazone, Mofebutazone, Oxyphenbutazone,Phenylbutazone, Phenyl Pyrazolidininones, Suxibuzone andThiazolinobutazone;

Salicylic Acid Derivatives such as Bromosaligenin, Fendosal, GlycolSal;icylate, Mesalamine, 1-Naphthyl Salicylate, Olsalazine andSulfasalazine;

Thiazinecarboxamides such as Droxicam, Isoxicam and Piroxicam;

Others such as e-Acetamidocaproic Acid, S-Adenosylmethionine,3-Amino4-hydroxybutyric Acid, Amixetrine, Bendazac, Bucolome,Carbazones, Difenpiramide, Ditazol, Guaiazulene, Heterocyclic AminoalkylEsters of Mycophenolic Acid and Derivatives, Nabumetone, Nimesulide,Orgotein, Oxaceprol, Oxazole Derivatives, Paranyline, Pifoxime,2-substituted-4, 6-di-tertiary-butyl-s-hydroxy-1,3-pyrimidines,Proquazone and Tenidap.

g. Antiseptics

Guanidines such as Alexidine, Ambazone, Chlorhexidine and Picloxydine;

Halogens/Halogen Compounds such as Bornyl Chloride, Calcium Iodate,Iodine, Iodine Monochloride, Iodine Trichloride, lodoform,Povidone-Iodine, Sodium Hypochlorite, Sodium Iodate, Symclosene, ThymolIodide, Triclocarban, Triclosan and Troclosene Potassium;

Nitrofurans such as Furazolidone, 2-(Methoxymethyl)-5-Nitrofuran,Nidroxyzone, Nifuroxime, Nifurzide and Nitrofurazone;

Phenols such as Acetomeroctol, Chloroxylenol Hexachlorophene, 1-NaphthylSalicylate, 2,4,6-Tribromo-m-cresol and3′,4′,5--Trichlorosalicylanilide;

Quinolines such as Aminoquinuride, Chloroxine, Chlorquinaldol,Cloxyquin, Ethylhydrocupreine, Halquinol, Hydrastine, 8-Hydroxyquinolineand Sulfate; and

others, such as Boric Acid, Chloroazodin, m-Cresyl Acetate, Cupricsulfate and Ichthammol.

h. Antivirals

Purines Pyrimidinones, such as 2-Acetyl-Pyridine5-((2-pyridylamino)thiocarbonyl) Thiocarbonohydrazone, Acyclovir,Dideoxyadenosine, dideoxycytidine, Dideoxyinosine, Edoxudine,Floxuridine, Ganciclovir, Idoxuridine, MADU, Pyridinone, Trifluridine,Vidrarbine and Zidovudline;

Others such as Acetylleucine Monoethanolamine, Acridinamine,Alkylisooxazoles, Amantadine, Amidinomycin, CuminaldehydeThiosemicarbzone, Foscarnet Sodium, Kethoxal, Lysozyme, Methisazone,Moroxydine, Podophyllotoxin, Ribavirin, Rimantadine, Stallimycin,Statolon, Thymosins, Tromantadine and Xenazoic Acid.

Combinations and Kits

The compounds and compositions containing the compounds may also becoated on bandages, mixed with bioadhesives or included in dressings.Thus, combinations of bandages, bioadhesives, dressings and other suchmaterials and the compositions formulated as described herein areprovided. Kits containing these combinations, which may also includecompositions containing the above listed agents, are also provided.

Methods of Treatment

Compositions for use with human skin preferably may be applied at leastonce per day, or if necessary, to achieve the desired result, moreoften, to the areas of the skin for which treatment is sought. It isunderstood that the precise treatment regimen depends upon theindividual treated and may be ascertained empirically depending upon theformulation, and particularly, the age of the treated individual. Anyregimen is acceptable as long as the desired anti-hyperalgesic effectsare achieved without substantial deleterious or sustained undesirableside effects.

The methods for treating human skin are practiced by applying to theskin, preferably at least daily, a composition suitable for human skintreatment or treatment of mucosal membranes and other body surfacetissues, including the vagina, rectum, mouth, eyes and other suchtissues. The compositions may be injected into joints or other inflamedareas.

Compositions may be combined with bandages, bioadhesives and otherdressings and applied to the body in combination therewith.

The following examples are included for illustrative purposes only andare not intended to limit the scope of the invention.

EXAMPLE A

Capsules

Active Compound 2.5 gm Corn starch 23.0 gm Lactose 145.0 gm Talc 15.0 gmMagnesium stearate 3.0 gm

The ingredients were mixed and were encapsulated using techniquespracticed in the art.

EXAMPLE B

Tablet

Active Compound 150 gm Lactose 125 gm Corn starch 50 gm Magnesiumstearate 2.0 gm Liquid Petrolatum 2.0 gm

The ingredients were mixed, then put through U.S. Standard Screens toproduce fine granules. The granules were compressed into tablets, eachtablet containing about 150 mg of an active compound of the presentinvention.

EXAMPLE C

Syrup

Active Compound 25 gm Lemon Oil 2 ml Sucrose 650 gm Citric Acid 4 gmBenzoic Acid 3 gm Tragacanth 16 gm Deionized water q.s. 1000 ml

The ingredients, without the active compound, are dispersed in water tomake about 800 to 900 ml of solution. The active compound is then addedand the solution is stirred into a syrup. Water is then added to make1000 ml of the syrup.

EXAMPLE D

Parenteral Solution

Active Compound 30 gm Methylparaben 3 gm Propylparaben 1 gm Lidocaine 5gm Deionized water q.s. 1000 ml

The ingredients are dissolved in water to provide a solution followed bysterilization by filtration.

EXAMPLE E

Rectal Suppository

Active Compound 80 gm Propylene glycol 95 gm Polyethylene glycol 40001800 gm

The active compound is added to the propylene glycol and milled until afinely divided uniform mixture is formed. The polyethylene glycol 4000is melted and the propylene glycol dispersion is added with stirring toobtain a suspension. The suspension is poured into molds, allowed tosolidify and removed from the molds for packaging.

EXAMPLE F

Water-washable Ointment

Active Compound 1.4% w/w Lanolin alcohol 0.15 w/w Emulsifying wax NF7.5% w/w PEG-20 glycerides 5.0% w/w Petrolatum 86.0% w/w

The ingredients are melted together and mixed well until the resultingointment congeals.

EXAMPLE G

Oil-in-water Cream

Active Compound 10.0% w/w Benzyl alcohol 4.0% w/w Propylene alcohol10.0% w/w Polyethylene glycol 400 10.0% w/w Petrolatum 20.0% w/w Stearylalcohol 10.0% w/w Poloxamer 10.0% w/w Water q.s. 100 Buffer to pH 7.0%w/w

In preparing the oil-in-water cream, water, propylene glycol andpolyethylene glycol 400 are heated to about 70 to 80° C., followed byadding a mixture of petrolatum, stearyl alcohol and poloxamer and themixture is stirred until homogeneous. The active compound in benzylalcohol is added and the mixture is homogenized. The pH is then adjustedwith a buffer to about 7.0.

EXAMPLE H

Aqueous gel

Active Compound 10.0% w/w Benzyl alcohol 4.0% w/w Hydroxyethyl cellulose3.0% w/w Water q.s. 100 Buffer to pH 7.0% w/w

The aqueous gel is prepared by mixing the active compound, benzylalcohol and adding the mixture to buffered water. Hydroxyethyl celluloseis then added with stirring until the mixture gels.

Having described the invention with reference to its preferredembodiments, it is to be understood that modifications within the scopeof the invention will be apparent to those skilled in the art.

What is claimed is:
 1. A method for the treatment of pruritus in a patient comprising administering to said patient an effective amount of a compound of formula IIA or a pharmaceutically acceptable salt thereof

wherein n=1-3, R₁ and R₂ are independently ═CH₃; —(CH₂)_(m), where m=4-8, —CH₂CH(OR)(CH₂)₂— wherein R is H, alkyl, acyl or aroyl; CH₂CH(F)(CH₂)₂—; —(CH₂)₂O(CH₂)₂—; or —(CH₂)₂CH═CHCH₂—; Ar=mono- or di-substituted phenyl; wherein said substituents are selected from the group consisting of halogen, OCH₃, OH, SO₂CH₃, CF₃, NH₂, alkyl, CN, unsubstituted and substituted sulfamoyl groups; or Ar substituted with —NH(CH₂)_(u)CO₂R′; —NH(CH₂)_(u)(CH═CH)_(u)(CH₂)CO₂R′; —NHCO(CH₂)_(u)(CH═CH)_(u)(CH₂)_(u)CO₂R′; —NHP(O)(OBn)₂; —NHP(O)(OR′)₂; —(CH₂)_(u)NHSO₂CH₃; —(CH₂)_(u)NHC(S)NHCH(CO₂R′)(CH₂)_(u)CO₂R′; —CONHOH; or —(CH₂)_(u)CONHOH;  wherein u=0-5; R′=H or lower alkyl; or Ar is

R₆=—H or —Ac X₈=—CO₂H; —NHSO₂CH₃; —NHP(O)(OBn)₂; —NHP(O)(OH)₂; —OP(O)(OBn)₂; or —OP(O)(OH)₂; R₇=—NH(CH₂)_(v)CO₂H; —NH(CH₂)_(v)CH(NH₂)(CO₂H); —NHCH(CO₂H)(CH₂)_(v)NH₂; —NH(CH₂)_(v)SO₃H; —NH(CH₂)_(v)PO₃H₂; —NH(CH₂)_(v)NHC(NH)NH₂; or —NHCH(CO₂H)(CH₂)_(v)CO₂H; and v=1-20; X₄ and X₅ are independently H; halogen; OH; OCH₃; CF₃; NO2; NH₂; amino substituted with acyl, carbamate, alkyl or aryl sulfonates; COR′ where R′ is OH, amide, alkoxy, aryloxy or heteroaryloxy, in a pharmaceutically acceptable carrier. 